U.S. patent number 9,199,943 [Application Number 13/869,316] was granted by the patent office on 2015-12-01 for 2-(poly-substituted aryl)-6-amino-5-halo-4-pyrimidinecarboxylic acids and their use as herbicides.
This patent grant is currently assigned to Dow AgroSciences, LLC.. The grantee listed for this patent is Terry W. Balko, Jeffrey B. Epp, James M. Ruiz, Paul R. Schmitzer, Thomas L. Siddall, Carla N. Yerkes. Invention is credited to Terry W. Balko, Jeffrey B. Epp, James M. Ruiz, Paul R. Schmitzer, Thomas L. Siddall, Carla N. Yerkes.
United States Patent |
9,199,943 |
Epp , et al. |
December 1, 2015 |
2-(poly-substituted aryl)-6-amino-5-halo-4-pyrimidinecarboxylic
acids and their use as herbicides
Abstract
6-Amino-5-halo-4-pyrimidinecarboxylic acids having
poly-substituted aryl substituents in the 2-position, and their
amine and acid derivatives, are potent herbicides demonstrating a
broad spectrum of weed control.
Inventors: |
Epp; Jeffrey B. (Noblesville,
IN), Schmitzer; Paul R. (Indianapolis, IN), Ruiz; James
M. (Westfield, IN), Balko; Terry W. (Greenfield, IN),
Siddall; Thomas L. (Zionsville, IN), Yerkes; Carla N.
(Crawfordsville, IN) |
Applicant: |
Name |
City |
State |
Country |
Type |
Epp; Jeffrey B.
Schmitzer; Paul R.
Ruiz; James M.
Balko; Terry W.
Siddall; Thomas L.
Yerkes; Carla N. |
Noblesville
Indianapolis
Westfield
Greenfield
Zionsville
Crawfordsville |
IN
IN
IN
IN
IN
IN |
US
US
US
US
US
US |
|
|
Assignee: |
Dow AgroSciences, LLC.
(Indianapolis, IN)
|
Family
ID: |
37951727 |
Appl.
No.: |
13/869,316 |
Filed: |
April 24, 2013 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20130237422 A1 |
Sep 12, 2013 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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13611304 |
Sep 12, 2012 |
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12984205 |
Jan 4, 2011 |
8288318 |
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12370633 |
Feb 13, 2009 |
7888287 |
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11973543 |
Oct 9, 2007 |
7538214 |
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11653021 |
Jan 12, 2007 |
7300907 |
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60758671 |
Jan 13, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
239/42 (20130101); C07F 9/6512 (20130101); A01N
43/54 (20130101); C07D 401/04 (20130101); C07D
403/04 (20130101) |
Current International
Class: |
C07D
239/42 (20060101); C07D 401/04 (20060101); C07D
403/04 (20060101); A01N 43/54 (20060101) |
Field of
Search: |
;544/326,329
;504/239 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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PCT/US2007/000916 |
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May 2007 |
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WO |
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WO2007/092184 |
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Aug 2007 |
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WO |
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Primary Examiner: Balasubramanian; Venkataraman
Attorney, Agent or Firm: Chang; Robert
Parent Case Text
RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No.
13/611,304 filed Sep. 12, 2012, now abandoned, which is a
continuation of U.S. application Ser. No. 12/984,205 filed Jan. 4,
2011 and issued as U.S. Pat. No. 8,288,318, which is a continuation
of U.S. application Ser. No. 12/370,633, filed Feb. 13, 2009 and
issued as U.S. Pat. No. 7,888,287, which is a divisional of U.S.
application Ser. No. 11/973,543 filed Oct. 9, 2007 and issued as
U.S. Pat. No. 7,538,214, which is a continuation of U.S.
application Ser. No. 11/653,021 filed Jan. 12, 2007 and issued as
U.S. Pat. No. 7,300,907, and claims the benefit of U.S. Provisional
Application No. 60/758,671 filed Jan. 13, 2006, all of which are
incorporated herein by reference in their entireties.
Claims
We claim:
1. A compound of Formula I: ##STR00017## wherein Q represents Cl;
R.sub.1 and R.sub.2 independently represent H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6 alkynyl, hydroxy,
C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 carboalkoxy, C.sub.1-C.sub.6 alkylcarbamyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 trialkylsilyl or
C.sub.1-C.sub.6 dialkyl phosphonyl or R.sub.1 and R.sub.2 taken
together with N represent a 5- or 6-membered saturated ring; and Ar
represents ##STR00018## wherein W.sub.2 represents F or Cl; X.sub.2
represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkylthio or
--NR.sub.3R.sub.4; Y.sub.2 represents Cl; and R.sub.3 and R.sub.4
independently represent H or C.sub.1-C.sub.4 alkyl; and R.sup.A
represents H or C1-C4-alkyl.
2. The compound of claim 1, wherein the compound is ##STR00019##
##STR00020## ##STR00021##
3. The compound of claim 1, wherein the compound is:
##STR00022##
4. The compound of claim 1, wherein the compound is:
##STR00023##
5. The compound of claim 1, wherein the compound is:
##STR00024##
6. The compound of claim 1, wherein the compound is:
##STR00025##
7. The compound of claim 1, wherein the compound is:
##STR00026##
8. The compound of claim 1, wherein the compound is:
##STR00027##
9. The compound of claim 1, wherein the compound is:
##STR00028##
10. The compound of claim 1, wherein the compound is:
##STR00029##
11. The compound of claim 1, wherein the compound is:
##STR00030##
12. The compound of claim 1, wherein the compound is:
##STR00031##
13. The compound of claim 1, wherein the compound is:
##STR00032##
14. The compound of claim 1, wherein the compound is:
##STR00033##
15. The compound of claim 1, wherein the compound is:
##STR00034##
16. The compound of claim 1, wherein the compound is:
##STR00035##
17. The compound of claim 1, wherein the compound is:
##STR00036##
18. The compound of claim 1, wherein the compound is:
##STR00037##
19. The compound of claim 1, wherein the compound is:
##STR00038##
20. A herbicidal composition comprising a herbicidally effective
amount of a compound of claim 1 and an agriculturally acceptable
adjuvant or carrier.
21. A method of controlling undesirable vegetation comprising (a)
post-emergently contacting the vegetation or locus thereof or (b)
pre-emergently contacting the area where the undesirable vegation
is to be controlled a herbicidally effective amount of the compound
of claim 1.
22. The method of claim 21, wherein the undesirable vegetation is
controlled by post-emergently contacting the vegetation of locus
thereof.
23. The method of claim 21, wherein the undesirable vegetation is
controlled by pre-emergently contacting the area where the
undesirable vegation is to be controlled.
24. The method of claim 21, wherein (a) or (b) is performed in the
presence of rice, wherein the rice is not injured.
25. The method of claim 24, wherein the rice is not injured one to
twenty days after performing (a) or (b).
26. The method of claim 21, wherein (a) or (b) is performed in the
presence of rice, wherein the rice is injured to a lesser extent
than the undesirable vegetation.
27. The method of claim 21, wherein (a) or (b) is performed in the
presence of wheat or barley, wherein the wheat or barley is not
injured.
28. The method of claim 27, wherein the wheat or barley is not
injured one to twenty days after performing (a) or (b).
29. The method of claim 21, wherein (a) or (b) is performed in the
presence of wheat or barley, wherein the wheat or barley is injured
to a lesser extent than the undesirable vegetation.
30. The method of claim 21, wherein the undesirable vegetation is
CHEAL, ABUTH, HELAN, LAMPU, PAPRH, VERPE, SCPJU, CYPDI, or MOOVA.
Description
BACKGROUND OF THE INVENTION
This invention relates to certain novel 2-(poly-substituted
aryl)-6-amino-5-halo-4-pyrimidinecarboxylates and their derivatives
and to the use of these compounds as herbicides.
A number of pyrimidinecarboxylic acids and their pesticidal
properties have been described in the art. WO 2005/063721 A1
discloses a genus of 2-substituted-6-amino-4-pyrimidinecarboxylic
acids and their derivatives and their use as herbicides. It has now
been discovered that certain particular subclasses of the genus
disclosed in '721 have greatly improved herbicidal activity and
selectivity.
SUMMARY OF THE INVENTION
It has now been found that certain 2-(poly-substituted
aryl)-6-amino-5-halo-4-pyrimidinecarboxylic acids and their
derivatives are superior herbicides with a broad spectrum of weed
control against woody plants, grasses and sedges as well as
broadleafs and with excellent crop selectivity. The compounds
further possess excellent toxicological or environmental
profiles.
The invention includes compounds of Formula I:
##STR00001## wherein
Q represents a halogen;
R.sub.1 and R.sub.2 independently represent H, C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6 alkynyl, hydroxy,
C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 carboalkoxy, C.sub.1-C.sub.6 alkylcarbamyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 trialkylsilyl or
C.sub.1-C.sub.6 dialkyl phosphonyl or R.sub.1 and R.sub.2 taken
together with N represent a 5- or 6-membered saturated ring;
and
Ar represents a polysubstituted aryl group selected from the group
consisting of
##STR00002## wherein
W.sub.1 represents F or Cl;
X.sub.1 represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkylthio or
--NR.sub.3R.sub.4;
Y.sub.1 represents halogen or C.sub.1-C.sub.4 haloalkyl or, when
X.sub.1 and Y.sub.1 are taken together, represents
--O(CH.sub.2).sub.nO-- wherein n=1 or 2; and
R.sub.3 and R.sub.4 independently represent H or C.sub.1-C.sub.4
alkyl;
##STR00003## wherein
W.sub.2 represents F or Cl;
X.sub.2 represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkylthio or
--NR.sub.3R.sub.4;
Y.sub.2 represents halogen or C.sub.1-C.sub.4 haloalkyl or, when
X.sub.2 and Y.sub.2 are taken together, represents
--O(CH.sub.2).sub.nO-- wherein n=1 or 2; and
R.sub.3 and R.sub.4 independently represent H or C.sub.1-C.sub.4
alkyl; and
##STR00004## wherein
Y.sub.3 represents halogen or C.sub.1-C.sub.4 haloalkyl or, when
Y.sub.3 and Z.sub.3 are taken together, represents
--O(CH.sub.2).sub.nO-- wherein n=1 or 2;
Z.sub.3 represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkylthio or
--NR.sub.3R.sub.4; and
R.sub.3 and R.sub.4 independently represent H or C.sub.1-C.sub.4
alkyl; and agriculturally acceptable derivatives of the carboxylic
acid group.
Compounds of Formula I wherein Q represents Cl and Br, wherein
X.sub.1 or X.sub.2 represent an alkoxy or --NR.sub.3R.sub.4,
wherein Y.sub.1, Y.sub.2 or Y.sub.3 represent Cl and wherein Ar
represents a 2,3,4-trisubstituted phenyl or a
2-fluoro-(4,5,6)-tetrasubstituted phenyl are independently
preferred.
The invention includes herbicidal compositions comprising an
herbicidally effective amount of a compound of Formula I and
agriculturally acceptable derivatives of the carboxylic acid group
in admixture with an agriculturally acceptable adjuvant or carrier.
The invention also includes a method of use of the compounds and
compositions of the present invention to kill or control
undesirable vegetation by application of an herbicidal amount of
the compound to the vegetation or to the locus of the vegetation as
well as to the soil prior to emergence of the vegetation.
DETAILED DESCRIPTION OF THE INVENTION
The herbicidal compounds of the present invention are derivatives
of 6-amino-5-halo-4-pyrimidinecarboxylic acids of the formula:
##STR00005## wherein
Q represents a halogen; and
Ar represents a polysubstituted aryl group selected from the group
consisting of
##STR00006## wherein
W.sub.1 represents F or Cl;
X.sub.1 represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkylthio or
--NR.sub.3R.sub.4;
Y.sub.1 represents halogen or C.sub.1-C.sub.4 haloalkyl or, when
X.sub.1 and Y.sub.1 are taken together, represents
--O(CH.sub.2).sub.nO-- wherein n=1 or 2; and
R.sub.3 and R.sub.4 independently represent H or C.sub.1-C.sub.4
alkyl;
##STR00007## wherein
W.sub.2 represents F or Cl;
X.sub.2 represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkylthio or
--NR.sub.3R.sub.4;
Y.sub.2 represents halogen or C.sub.1-C.sub.4 haloalkyl or, when
X.sub.2 and Y.sub.2 are taken together, represents
--O(CH.sub.2).sub.nO-- wherein n=1 or 2; and
R.sub.3 and R.sub.4 independently represent H or C.sub.1-C.sub.4
alkyl; and
##STR00008## wherein
Y.sub.3 represents halogen or C.sub.1-C.sub.4 haloalkyl or, when
Y.sub.3 and Z.sub.3 are taken together, represents
--O(CH.sub.2).sub.nO-- wherein n=1 or 2;
Z.sub.3 represents C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 haloalkylthio or
--NR.sub.3R.sub.4; and
R.sub.3 and R.sub.4 independently represent H or C.sub.1-C.sub.4
alkyl.
These compounds are characterized by possessing a halogen in the
5-position and a tri- or tetra-substituted aryl group in the
2-position of the pyrimidine ring. Preferred substituted aryl
groups include 2,3,4-trisubstituted phenyl and
2-fluoro-(4,5,6)-tetrasubstituted phenyl groups.
The amino group at the 6-position of the pyrimidine ring can be
unsubstituted or substituted with one or more C.sub.1-C.sub.6
alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6 alkynyl, hydroxy,
C.sub.1-C.sub.6 alkoxy or amino substituents. The amino group can
be further derivatized as an amide, a carbamate, a urea, a
sulfonamide, a silylamine or a phosphoramidate. Such derivatives
are capable of breaking down into the amine. An unsubstituted amino
group or one substituted with one or two alkyl substituents is
preferred.
The carboxylic acids of Formula I are believed to be the compounds
that actually kill or control undesirable vegetation and are
typically preferred. Analogs of these compounds in which the acid
group of the pyrimidine carboxylic acid is derivatized to form a
related substituent that can be transformed within plants or the
environment to an acid group possess essentially the same
herbicidal effect and are within the scope of the invention.
Therefore, an "agriculturally acceptable derivative", when used to
describe the carboxylic acid functionality at the 4-position, is
defined as any salt, ester, acylhydrazide, imidate, thioimidate,
amidine, amide, orthoester, acylcyanide, acyl halide, thioester,
thionoester, dithiolester, nitrile or any other acid derivative
well known in the art which (a) does not substantially affect the
herbicidal activity of the active ingredient, i.e., the
2-aryl-6-amino-5-halo-4-pyrimidinecarboxylic acid, and (b) is or
can be hydrolyzed, oxidized or metabolized in plants or soil to the
4-pyrimidinecarboxylic acid of Formula I that, depending upon the
pH, is in the dissociated or the undissociated form. The preferred
agriculturally acceptable derivatives of the carboxylic acid are
agriculturally acceptable salts, esters and amides. Likewise, an
"agriculturally acceptable derivative", when used to describe the
amine functionality at the 6-position, is defined as any salt,
silylamine, phosphorylamine, phosphinimine, phosphoramidate,
sulfonamide, sulfilimine, sulfoximine, aminal, hemiaminal, amide,
thioamide, carbamate, thiocarbamate, amidine, urea, imine, nitro,
nitroso, azide, or any other nitrogen containing derivative well
known in the art which (a) does not substantially affect the
herbicidal activity of the active ingredient, i.e., the
2-aryl-6-amino-5-halo-4-pyrimidinecarboxylic acid, and (b) is or
can be hydrolyzed in plants or soil to a free amine of Formula I.
N-Oxides which are also capable of breaking into the parent
pyrimidine of Formula I are also covered by the scope of this
invention.
Suitable salts include those derived from alkali or alkaline earth
metals and those derived from ammonia and amines. Preferred cations
include sodium, potassium, magnesium, and aminium cations of the
formula: R.sub.5R.sub.6R.sub.7NH.sup.+ wherein R.sub.5, R.sub.6,
and R.sub.7 each, independently represents hydrogen or
C.sub.1-C.sub.12 alkyl, C.sub.3-C.sub.12 alkenyl or
C.sub.3-C.sub.12 alkynyl, each of which is optionally substituted
by one or more hydroxy, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkylthio or phenyl groups, provided that R.sub.5, R.sub.6, and
R.sub.7 are sterically compatible. Additionally, any two of
R.sub.5, R.sub.6, and R.sub.7 together may represent an aliphatic
difunctional moiety containing 1 to 12 carbon atoms and up to two
oxygen or sulfur atoms. Salts of the compounds of Formula I can be
prepared by treatment of compounds of Formula I with a metal
hydroxide, such as sodium hydroxide, or an amine, such as ammonia,
trimethylamine, diethanolamine, 2-methylthiopropylamine,
bisallylamine, 2-butoxyethylamine, morpholine, cyclododecylamine,
or benzylamine Amine salts are often preferred forms of the
compounds of Formula I because they are water-soluble and lend
themselves to the preparation of desirable aqueous based herbicidal
compositions.
Suitable esters include those derived from C.sub.1-C.sub.12 alkyl,
C.sub.3-C.sub.12 alkenyl or C.sub.3-C.sub.12 alkynyl alcohols, such
as methanol, iso-propanol, butanol, 2-ethylhexanol, butoxyethanol,
methoxypropanol, allyl alcohol, propargyl alcohol or cyclohexanol.
Esters can be prepared by coupling of the 4-pyrimidine carboxylic
acids with the alcohol using any number of suitable activating
agents such as those used for peptide couplings such as
dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI), by
reacting the corresponding acid chloride of a
4-pyrimidinecarboxylic acid of Formula I with an appropriate
alcohol, by reacting the corresponding 4-pyrimidinecarboxylic acid
of Formula I with an appropriate alcohol in the presence of an acid
catalyst or by transesterification. Suitable amides include those
derived from ammonia or from C.sub.1-C.sub.12 alkyl,
C.sub.3-C.sub.12 alkenyl or C.sub.3-C.sub.12 alkynyl mono- or
di-substituted amines, such as but not limited to dimethylamine,
diethanolamine, 2-methylthiopropylamine, bisallylamine,
2-butoxyethylamine, cyclododecylamine, benzylamine or cyclic or
aromatic amines with or without additional heteroatoms such as but
not limited to aziridine, azetidine, pyrrolidine, pyrrole,
imidazole, tetrazole or morpholine. Amides can be prepared by
reacting the corresponding 4-pyrimidinecarboxylic acid chloride,
mixed anhydride, or carboxylic ester of Formula I with ammonia or
an appropriate amine.
The terms "alkyl", "alkenyl" and "alkynyl", as well as derivative
terms such as "alkoxy", "acyl", "alkylthio" and "alkylsulfonyl", as
used herein, include within their scope straight chain, branched
chain and cyclic moieties. The terms "alkenyl" and "alkynyl" are
intended to include one or more unsaturated bonds.
The term "aryl", as well as derivative terms such as "aryloxy",
refers to a phenyl.
Unless specifically limited otherwise, the term "halogen" including
derivative terms such as "halo" refers to fluorine, chlorine,
bromine, and iodine.
The terms "haloalkyl" and "haloalkoxy" refer to alkyl and alkoxy
groups substituted with from 1 to the maximum possible number of
halogen atoms.
The compounds of Formula I can be made using well-known chemical
procedures. The required starting materials are commercially
available or readily synthesized utilizing standard procedures. In
the following synthesis schemes, the methyl esters of Formula I are
shown as the target compounds and are depicted as Formula IA (see
Scheme 1). Compounds of Formula I can be prepared from compounds of
Formula IA by the method illustrated in Example 37.
As shown in Scheme 1, the
2-aryl-6-amino-5-halo-4-pyrimidine-carboxylic acid esters of
Formula IA can be made from compounds of Formula II by reaction
with a halogenating reagent such as N-bromosuccinimide in a solvent
such as chloroform or with
1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]-octane
bis(tetrafluoroborate) (F-TEDA; SELECTFLUOR.TM. fluorinating agent)
in a solvent such as acetonitrile. The method of Scheme 1 is
illustrated in Examples 33 and 34.
##STR00009##
As shown in Scheme 2, the 2-aryl-6-amino-4-pyrimidinecarboxylic
acid esters of Formula IA (Q.sub.1=halogen) as well as compounds of
Formula II (Q.sub.1=H) can be prepared by reaction of an
appropriately substituted pyrimidine of Formula III with a facile
leaving group L, and an organometallic compound of type IV in an
inert solvent in the presence of a transition metal catalyst.
##STR00010##
In this case Q.sub.1 can be hydrogen or a halogen; L can be
chlorine, bromine, iodine or trifluoromethanesulfonate; M can be
tri-(C.sub.1-C.sub.4 alkyl)tin or B(OR.sub.8)(OR.sub.9), where
R.sub.8 and R.sub.9 are independently of one another, hydrogen,
C.sub.1-C.sub.6 alkyl, or when taken together form an ethylene or
propylene group; and "Catalyst" can be a transition metal catalyst,
in particular a palladium catalyst such as
bis(triphenylphosphine)palladium(II)dichloride. The method of
Scheme 2 is illustrated in Examples 31 and 32.
Alternatively, as shown in Scheme 3, the
2-aryl-6-amino-5-halo-4-pyrimidinecarboxylic acid esters of Formula
IA can be prepared from appropriately substituted type V compounds
possessing a facile leaving group in the 2-position by reaction
with an organometallic compound of type IV in an inert solvent in
the presence of a transition metal catalyst; followed by oxidation
of the intermediate thioether VI to either sulfoxide or sulfone;
followed by reaction with various amines (VII). In this case, Q is
a halogen; R.sub.10 can be an alkyl or aryl group; L can be
chlorine, bromine, iodo or trifluoromethanesulfonate; M can be
tri-(C.sub.1-C.sub.4 alkyl)tin or B(OR.sub.8)(OR.sub.0), where
R.sub.8 and R.sub.9 are independently of one another, hydrogen,
C.sub.1-C.sub.6 alkyl, or when taken together form an ethylene or
propylene group; and "Catalyst" can be a transition metal catalyst,
in particular a palladium catalyst such as
bis(triphenylphosphine)palladium(II)dichloride. The method of
Scheme 3 is illustrated in Examples 27 and 28.
##STR00011##
Alternatively, as shown in Scheme 4, the
2-aryl-6-amino-5-halo-4-pyrimidinecarboxylic acid esters of Formula
IA can be prepared from appropriately substituted type VIII
compounds substituted with a metal in the
##STR00012## 2-position by reaction with an aryl compound of type
IX in an inert solvent in the presence of a transition metal
catalyst; followed by oxidation of the intermediate thioether X to
either sulfoxide or sulfone; followed by reaction with various
amines (VII). In this case, Q is a halogen; R.sub.10 can be an
alkyl or aryl group; L can be chlorine, bromine, iodine or
trifluoromethanesulfonate; M can be tri-(C.sub.1-C.sub.4 alkyl)tin;
and "Catalyst" can be a transition metal catalyst, in particular a
palladium catalyst such
bis(triphenylphosphine)palladium(II)dichloride. The method of
Scheme 4 is illustrated in Examples 29 and 30.
The coupling of III+IV, V+IV, and VIII+IX may, where appropriate,
be followed by reactions on either ring to obtain further
derivatives of the compounds of Formula IA.
As shown in Scheme 5, appropriately substituted pyrimidines of
Formula III where Q.sub.1 is a halogen and L is chloro or bromo can
be obtained by reaction of pyrimidine XI (Q.sub.1 is a halogen and
L is chloro or bromo) with amines of type VII. Also shown in Scheme
5, appropriately substituted pyrimidines of Formula V where Q.sub.1
is halogen; R.sub.10 is an alkyl or aryl group; and L is chloro or
bromo can be easily obtained by reaction of pyrimidine XI (Q.sub.1
is halogen and L is chloro or bromo) with thiolate salts of type
XII in solvent system consisting of a mixture of benzene and
water.
##STR00013##
Also shown in Scheme 5, appropriately substituted pyrimidines of
Formula III where Q.sub.1 is a hydrogen and L is chloro or bromo
can be prepared by reaction of pyrimidines of Formula XI (Q.sub.1
is a hydrogen and L is chloro or bromo) with thiolate salts of type
XII in a solvent system consisting of a mixture of benzene and
water; followed by oxidation of the intermediate thioether XIII;
followed by reaction with amines of type VII.
Finally shown in Scheme 5, appropriately substituted pyrimidines of
Forumla VIII where Q.sub.1 is a halogen; R.sub.10 is an alkyl or
aryl group; and M is trimethyltin can be made by reaction of V
(Q.sub.1 is a halogen and L is chloro or bromo) with
hexamethylditin in an inert solvent such as dioxane in the presence
of a transition metal catalyst such as
bis(triphenylphosphine)palladium(II)dichloride. The methods of
Scheme 5 are illustrated in Examples 21-26.
As shown in Scheme 6, appropriately substituted pyrimidines of
Formula XI where Q.sub.1 is hydrogen or halogen and L is chloro or
bromo can be prepared from compounds of Formula XIV (Q.sub.1 is
hydrogen or chloro, see H. Gershon, J. Org. Chem. 1962, 27,
3507-3510 for preparation) by reaction with reagents such as
phosphorous oxychloride or phosphorous oxybromide. The reaction can
be run neat or in the presence of a solvent such as sulfolane. The
method of Scheme 6 is illustrated in Example 20.
##STR00014##
For other methods to prepare compounds of Formula I, see WO
2005/063721 A1.
It is recognized that some reagents and reaction conditions
described above for preparing compounds of Formula I may not be
compatible with certain functionalitites present in the
intermediates. In these instances, the incorporation of
protection/deprotection sequences or functional group
interconversions into the synthesis will aid in obtaining the
desired products. The use and choice of the protection groups will
be apparent to one skilled in chemical synthesis.
One skilled in the art will recognize that, in some cases, after
the introduction of a given reagent as it is depicted in any
individual scheme, it may be necessary to perform additional
routine synthetic steps not described in detail to complete the
synthesis of compounds of Formula I. One skilled in the art will
also recognize that it may necessary to perform a combination of
the steps illustrated in the above schemes in an order other than
that implied by the particular sequence presented to prepare the
compounds of Formula I.
Finally, one skilled in the art will also recognize that compounds
of Formula I and the intermediates described herein can be
subjected to various electrophilic, nucleophilic, radical,
organometallic, oxidation, and reduction reactions to add
substituents or modify existing substituents.
The compounds of Formula I have been found to be useful as
pre-emergence and post-emergence herbicides. They can be employed
at non-selective (higher) rates of application to control a broad
spectrum of the vegetation in an area or at lower rates of
application for the selective control of undesirable vegetation.
Areas of application include pasture and rangelands, roadsides and
rights of way, power lines and any industrial areas where control
of undesirable vegetation is desirable. Another use is the control
of unwanted vegetation in crops such as corn, rice and cereals.
They can also be used to control undesirable vegetation in tree
crops such as citrus, apple, rubber, oil palm, forestry and others.
It is usually preferred to employ the compounds postemergence. It
is further usually preferred to use the compounds to control a wide
spectrum of woody plants, broadleaf and grass weeds, and sedges.
Use of the compounds to control undesirable vegetation in
established crops is especially indicated. While each of the
2-aryl-6-amino-5-halo-4-pyrimidinecarboxylate compounds encompassed
by Formula I is within the scope of the invention, the degree of
herbicidal activity, the crop selectivity, and the spectrum of weed
control obtained varies depending upon the substituents present. An
appropriate compound for any specific herbicidal utility can be
identified by using the information presented herein and routine
testing.
The term herbicide is used herein to mean an active ingredient that
kills, controls or otherwise adversely modifies the growth of
plants. An herbicidally effective or vegetation controlling amount
is an amount of active ingredient which causes an adversely
modifying effect and includes deviations from natural development,
killing, regulation, desiccation, retardation, and the like. The
terms plants and vegetation include germinant seeds, emerging
seedlings and established vegetation.
Herbicidal activity is exhibited by the compounds of the present
invention when they are applied directly to the plant or to the
locus of the plant at any stage of growth or before planting or
emergence. The effect observed depends upon the plant species to be
controlled, the stage of growth of the plant, the application
parameters of dilution and spray drop size, the particle size of
solid components, the environmental conditions at the time of use,
the specific compound employed, the specific adjuvants and carriers
employed, the soil type, and the like, as well as the amount of
chemical applied. These and other factors can be adjusted as is
known in the art to promote non-selective or selective herbicidal
action. Generally, it is preferred to apply the compounds of
Formula I postemergence to relatively immature undesirable
vegetation to achieve the maximum control of weeds.
Application rates of about 1 to about 1,000 g/Ha are generally
employed in postemergence operations; for preemergence
applications, rates of about 10 to about 2,000 g/Ha are generally
employed. The higher rates designated generally give non-selective
control of a broad variety of undesirable vegetation. The lower
rates typically give selective control and can be employed in the
locus of crops.
The herbicidal compounds of the present invention are often applied
in conjunction with one or more other herbicides to control a wider
variety of undesirable vegetation. When used in conjunction with
other herbicides, the presently claimed compounds can be formulated
with the other herbicide or herbicides, tank mixed with the other
herbicide or herbicides or applied sequentially with the other
herbicide or herbicides. Some of the herbicides that can be
employed in conjunction with the compounds of the present invention
include: amide herbicides such as allidochlor, beflubutamid,
benzadox, benzipram, bromobutide, cafenstrole, CDEA, chlorthiamid,
cyprazole, dimethenamid, dimethenamid-P, diphenamid, epronaz,
etnipromid, fentrazamide, flupoxam, fomesafen, halosafen,
isocarbamid, isoxaben, napropamide, naptalam, pethoxamid,
propyzamide, quinonamid and tebutam; anilide herbicides such as
chloranocryl, cisanilide, clomeprop, cypromid, diflufenican,
etobenzanid, fenasulam, flufenacet, flufenican, mefenacet,
mefluidide, metamifop, monalide, naproanilide, pentanochlor,
picolinafen and propanil; arylalanine herbicides such as
benzoylprop, flampropand flamprop-M; chloroacetanilide herbicides
such as acetochlor, alachlor, butachlor, butenachlor, delachlor,
diethatyl, dimethachlor, metazachlor, metolachlor, S-metolachlor,
pretilachlor, propachlor, propisochlor, prynachlor, terbuchlor,
thenylchlor and xylachlor; sulfonanilide herbicides such as
benzofluor, perfluidone, pyrimisulfan and profluazol; sulfonamide
herbicides such as asulam, carbasulam, fenasulam and oryzalin;
antibiotic herbicides such as bilanafos; benzoic acid herbicides
such as chloramben, dicamba, 2,3,6-TBA and tricamba;
pyrimidinyloxybenzoic acid herbicides such as bispyribac and
pyriminobac; pyrimidinylthiobenzoic acid herbicides such as
pyrithiobac; phthalic acid herbicides such as chlorthal; picolinic
acid herbicides such as aminopyralid, clopyralid and picloram;
quinolinecarboxylic acid herbicides such as quinclorac and
quinmerac; arsenical herbicides such as cacodylic acid, CMA, DSMA,
hexaflurate, MAA, MAMA, MSMA, potassium arsenite and sodium
arsenite; benzoylcyclohexanedione herbicides such as mesotrione,
sulcotrione, tefuryltrione and tembotrione; benzofuranyl
alkylsulfonate herbicides such as benfuresate and ethofumesate;
carbamate herbicides such as asulam, carboxazole chlorprocarb,
dichlormate, fenasulam, karbutilate and terbucarb; carbanilate
herbicides such as barban, BCPC, carbasulam, carbetamide, CEPC,
chlorbufam, chlorpropham, CPPC, desmedipham, phenisopham,
phenmedipham, phenmedipham-ethyl, propham and swep; cyclohexene
oxime herbicides such as alloxydim, butroxydim, clethodim,
cloproxydim, cycloxydim, profoxydim, sethoxydim, tepraloxydim and
tralkoxydim; cyclopropylisoxazole herbicides such as isoxachlortole
and isoxaflutole; dicarboximide herbicides such as benzfendizone,
cinidon-ethyl, flumezin, flumiclorac, flumioxazin and flumipropyn;
dinitroaniline herbicides such as benfluralin, butralin,
dinitramine, ethalfluralin, fluchloralin, isopropalin,
methalpropalin, nitralin, oryzalin, pendimethalin, prodiamine,
profluralin and trifluralin; dinitrophenol herbicides such as
dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen
and medinoterb; diphenyl ether herbicides such as ethoxyfen;
nitrophenyl ether herbicides such as acifluorfen, aclonifen,
bifenox, chlomethoxyfen, chlornitrofen, etnipromid, fluorodifen,
fluoroglycofen, fluoronitrofen, fomesafen, furyloxyfen, halosafen,
lactofen, nitrofen, nitrofluorfen and oxyfluorfen; dithiocarbamate
herbicides such as dazomet and metam; halogenated aliphatic
herbicides such as alorac, chloropon, dalapon, flupropanate,
hexachloroacetone, iodomethane, methyl bromide, monochloroacetic
acid, SMA and TCA; imidazolinone herbicides such as imazamethabenz,
imazamox, imazapic, imazapyr, imazaquin and imazethapyr; inorganic
herbicides such as ammonium sulfamate, borax, calcium chlorate,
copper sulfate, ferrous sulfate, potassium azide, potassium
cyanate, sodium azide, sodium chlorate and sulfuric acid; nitrile
herbicides such as bromobonil, bromoxynil, chloroxynil,
dichlobenil, iodobonil, ioxynil and pyraclonil; organophosphorus
herbicides such as amiprofos-methyl, anilofos, bensulide,
bilanafos, butamifos, 2,4-DEP, DMPA, EBEP, fosamine, glufosinate,
glyphosate and piperophos; phenoxy herbicides such as bromofenoxim,
clomeprop, 2,4-DEB, 2,4-DEP, difenopenten, disul, erbon,
etnipromid, fenteracol and trifopsime; phenoxyacetic herbicides
such as 4-CPA, 2,4-D, 3,4-DA, MCPA, MCPA-thioethyl and 2,4,5-T;
phenoxybutyric herbicides such as 4-CPB, 2,4-DB, 3,4-DB, MCPB and
2,4,5-TB; phenoxypropionic herbicides such as cloprop, 4-CPP,
dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, mecopropand
mecoprop-P; aryloxyphenoxypropionic herbicides such as chlorazifop,
clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P,
fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P,
isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P
and trifop; phenylenediamine herbicides such as dinitramine and
prodiamine; pyrazolyl herbicides such as benzofenap, pyrazolynate,
pyrasulfotole, pyrazoxyfen, pyroxasulfone and topramezone;
pyrazolylphenyl herbicides such as fluazolate and pyraflufen;
pyridazine herbicides such as credazine, pyridafol and pyridate;
pyridazinone herbicides such as brompyrazon, chloridazon,
dimidazon, flufenpyr, metflurazon, norflurazon, oxapyrazon and
pydanon; pyridine herbicides such as aminopyralid, cliodinate,
clopyralid, dithiopyr, fluoroxypyr, haloxydine, picloram,
picolinafen, pyriclor, thiazopyr and triclopyr; pyrimidinediamine
herbicides such as iprymidam and tioclorim; quaternary ammonium
herbicides such as cyperquat, diethamquat, difenzoquat, diquat,
morfamquat and paraquat; thiocarbamate herbicides such as butylate,
cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate,
methiobencarb, molinate, orbencarb, pebulate, prosulfocarb,
pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate and
vernolate; thiocarbonate herbicides such as dimexano, EXD and
proxan; thiourea herbicides such as methiuron; triazine herbicides
such as dipropetryn, triaziflam and trihydroxytriazine;
chlorotriazine herbicides such as atrazine, chlorazine, cyanazine,
cyprazine, eglinazine, ipazine, mesoprazine, procyazine,
proglinazine, propazine, sebuthylazine, simazine, terbuthylazine
and trietazine; methoxytriazine herbicides such as atraton,
methometon, prometon, secbumeton, simeton and terbumeton;
methylthiotriazine herbicides such as ametryn, aziprotryne,
cyanatryn, desmetryn, dimethametryn, methoprotryne, prometryn,
simetryn and terbutryn; triazinone herbicides such as ametridione,
amibuzin, hexazinone, isomethiozin, metamitron and metribuzin;
triazole herbicides such as amitrole, cafenstrole, epronaz and
flupoxam; triazolone herbicides such as amicarbazone, bencarbazone,
carfentrazone, flucarbazone, propoxycarbazone, sulfentrazone and
thiencarbazone-methyl; triazolopyrimidine herbicides such as
cloransulam, diclosulam, florasulam, flumetsulam, metosulam,
penoxsulam and pyroxsulam; uracil herbicides such as butafenacil,
bromacil, flupropacil, isocil, lenacil and terbacil;
3-phenyluracils; urea herbicides such as benzthiazuron, cumyluron,
cycluron, dichloralurea, diflufenzopyr, isonoruron, isouron,
methabenzthiazuron, monisouron and noruron; phenylurea herbicides
such as anisuron, buturon, chlorbromuron, chloreturon,
chlorotoluron, chloroxuron, daimuron, difenoxuron, dimefuron,
diuron, fenuron, fluometuron, fluothiuron, isoproturon, linuron,
methiuron, methyldymron, metobenzuron, metobromuron, metoxuron,
monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron,
tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides
such as amidosulfuron, azimsulfuron, bensulfuron, chlorimuron,
cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron,
flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron,
mesosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron,
primisulfuron, pyrazosulfuron, rimsulfuron, sulfometuron,
sulfosulfuron and trifloxysulfuron; triazinylsulfonylurea
herbicides such as chlorsulfuron, cinosulfuron, ethametsulfuron,
iodosulfuron, metsulfuron, prosulfuron, thifensulfuron,
triasulfuron, tribenuron, triflusulfuron and tritosulfuron;
thiadiazolylurea herbicides such as buthiuron, ethidimuron,
tebuthiuron, thiazafluoron and thidiazuron; and unclassified
herbicides such as acrolein, allyl alcohol, azafenidin, benazolin,
bentazone, benzobicyclon, buthidazole, calcium cyanamide,
cambendichlor, chlorfenac, chlorfenprop, chlorflurazole,
chlorflurenol, cinmethylin, clomazone, CPMF, cresol,
ortho-dichlorobenzene, dimepiperate, endothal, fluoromidine,
fluridone, fluorochloridone, flurtamone, fluthiacet, indanofan,
methazole, methyl isothiocyanate, nipyraclofen, OCH, oxadiargyl,
oxadiazon, oxaziclomefone, pentachlorophenol, pentoxazone,
phenylmercury acetate, pinoxaden, prosulfalin, pyribenzoxim,
pyriftalid, quinoclamine, rhodethanil, sulglycapin, thidiazimin,
tridiphane, trimeturon, tripropindan and tritac. The herbicidal
compounds of the present invention can, further, be used in
conjunction with glyphosate, glufosinate or 2,4-D on
glyphosate-tolerant, glufosinate-tolerant or 2,4-D-tolerant crops.
It is generally preferred to use the compounds of the invention in
combination with herbicides that are selective for the crop being
treated and which complement the spectrum of weeds controlled by
these compounds at the application rate employed. It is further
generally preferred to apply the compounds of the invention and
other complementary herbicides at the same time, either as a
combination formulation or as a tank mix.
The compounds of the present invention can generally be employed in
combination with known herbicide safeners, such as benoxacor,
benthiocarb, brassinolide, cloquintocet (mexyl), cyometrinil,
daimuron, dichlormid, dicyclonon, dimepiperate, disulfoton,
fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole,
isoxadifen-ethyl, mefenpyr-diethyl, MG 191, MON 4660, naphthalic
anhydride (NA), oxabetrinil, R29148 and N-phenyl-sulfonylbenzoic
acid amides, to enhance their selectivity. They can additionally be
employed to control undesirable vegetation in many crops that have
been made tolerant to or resistant to them or to other herbicides
by genetic manipulation or by mutation and selection. For example,
corn, wheat, rice, soybean, sugarbeet, cotton, canola, and other
crops that have been made tolerant or resistant to compounds that
are acetolactate synthase inhibitors in sensitive plants can be
treated. Many glyphosate and glufosinate tolerant crops can be
treated as well, alone or in combination with these herbicides.
Some crops (e.g. cotton) have been made tolerant to auxinic
herbicides such as 2,4-dichlorophenoxyacetic acid. These herbicides
may be used to treat such resistant crops or other auxin tolerant
crops.
While it is possible to utilize the
2-aryl-6-amino-5-halo-4-pyrimidinecarboxylate compounds of Formula
I directly as herbicides, it is preferable to use them in mixtures
containing an herbicidally effective amount of the compound along
with at least one agriculturally acceptable adjuvant or carrier.
Suitable adjuvants or carriers should not be phytotoxic to valuable
crops, particularly at the concentrations employed in applying the
compositions for selective weed control in the presence of crops,
and should not react chemically with the compounds of Formula I or
other composition ingredients. Such mixtures can be designed for
application directly to weeds or their locus or can be concentrates
or formulations that are normally diluted with additional carriers
and adjuvants before application. They can be solids, such as, for
example, dusts, granules, water dispersible granules, or wettable
powders, or liquids, such as, for example, emulsifiable
concentrates, solutions, emulsions or suspensions.
Suitable agricultural adjuvants and carriers that are useful in
preparing the herbicidal mixtures of the invention are well known
to those skilled in the art.
Liquid carriers that can be employed include water, toluene,
xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone,
cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate,
amyl acetate, butyl acetate, propylene glycol monomethyl ether and
diethylene glycol monomethyl ether, methanol, ethanol, isopropanol,
amyl alcohol, ethylene glycol, propylene glycol, glycerine, and the
like. Water is generally the carrier of choice for the dilution of
concentrates.
Suitable solid carriers include talc, pyrophyllite clay, silica,
attapulgus clay, kaolin clay, kieselguhr, chalk, diatomaceous
earth, lime, calcium carbonate, bentonite clay, Fuller's earth,
cotton seed hulls, wheat flour, soybean flour, pumice, wood flour,
walnut shell flour, lignin, and the like.
It is usually desirable to incorporate one or more surface-active
agents into the compositions of the present invention. Such
surface-active agents are advantageously employed in both solid and
liquid compositions, especially those designed to be diluted with
carrier before application. The surface-active agents can be
anionic, cationic or nonionic in character and can be employed as
emulsifying agents, wetting agents, suspending agents, or for other
purposes. Typical surface-active agents include salts of alkyl
sulfates, such as diethanol-ammonium lauryl sulfate;
alkylarylsulfonate salts, such as calcium dodecyl-benzenesulfonate;
alkylphenol-alkylene oxide addition products, such as
nonylphenol-C.sub.18 ethoxylate; alcohol-alkylene oxide addition
products, such as tridecyl alcohol-C.sub.16 ethoxylate; soaps, such
as sodium stearate; alkylnaphthalene-sulfonate salts, such as
sodium dibutylnaphthalenesulfonate; dialkyl esters of
sulfosuccinate salts, such as sodium
di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol
oleate; quaternary amines, such as lauryl trimethyl-ammonium
chloride; polyethylene glycol esters of fatty acids, such as
poly-ethylene glycol stearate; block copolymers of ethylene oxide
and propylene oxide; and salts of mono and dialkyl phosphate
esters.
Other adjuvants commonly used in agricultural compositions include
compatibilizing agents, antifoam agents, sequestering agents,
neutralizing agents and buffers, corrosion inhibitors, dyes,
odorants, spreading agents, penetration aids, sticking agents,
dispersing agents, thickening agents, freezing point depressants,
antimicrobial agents, and the like. The compositions may also
contain other compatible components, for example, other herbicides,
plant growth regulants, fungicides, insecticides, and the like and
can be formulated with liquid fertilizers or solid, particulate
fertilizer carriers such as ammonium nitrate, urea and the
like.
The concentration of the active ingredients in the herbicidal
compositions of this invention is generally from about 0.001 to
about 98 percent by weight. Concentrations from about 0.01 to about
90 percent by weight are often employed. In compositions designed
to be employed as concentrates, the active ingredient is generally
present in a concentration from about 5 to about 98 weight percent,
preferably about 10 to about 90 weight percent. Such compositions
are typically diluted with an inert carrier, such as water, before
application. The diluted compositions usually applied to weeds or
the locus of weeds generally contain about 0.0001 to about 1 weight
percent active ingredient and preferably contain about 0.001 to
about 0.05 weight percent.
The present compositions can be applied to weeds or their locus by
the use of conventional ground or aerial dusters, sprayers, and
granule applicators, by addition to irrigation water, and by other
conventional means known to those skilled in the art.
The following Examples are presented to illustrate the various
aspects of this invention and should not be construed as
limitations to the claims.
EXAMPLES
1. Preparation of 3-bromo-6-chloro-2-fluorophenol
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol)
in tetrahydrofuran (THF; 50 mL) was slowly added to lithium
diisopropylamide (LDA; 0.125 mol) in THF (600 mL) at -50.degree. C.
After addition, the solution was warmed to -20.degree. C. and then
cooled to -50.degree. C. A solution of trimethyl borate (13.5 g,
0.130 mol) in THF (20 mL) was added slowly and the temperature was
warmed to -20.degree. C. The mixture was then cooled to -70.degree.
C. and a solution of peracetic acid (32% in acetic acid, 0.150 mol)
was slowly added and the mixture was warmed to ambient temperature.
Water (250 mL) was added and the solution was extracted with ethyl
acetate (2.times.200 mL). The combined organic phases were dried
and concentrated. The black oil was purified by column
chromatography (20% ethyl acetate in hexanes) to give
3-bromo-6-chloro-2-fluorophenol (14.1 g, 0.063 mol) .sup.1H NMR
(CDCl.sub.3): .delta. 7.05 (m, 2H), 5.5 (br s, 1H).
Another phenol prepared according to the procedure of Example 1
was:
3-Bromo-2,6-dichlorophenol: mp 69-70.degree. C.
2. Preparation of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene
A heterogeneous mixture of 3-bromo-6-chloro-2-fluorophenol (14.4 g,
0.064 mol), methyl iodide (13.5 g, 0.096 mol) and potassium
carbonate (8.8 g, 0.064 mol) in acetonitrile (100 mL) was heated
under reflux for two hours. The mixture was cooled, diluted with
water (100 mL) and extracted with diethyl ether (2.times.150 mL).
The combined extracts were dried and concentrated. The dark oil was
purified by chromatography (5% ethyl acetate in hexanes) to give
1-bromo-4-chloro-2-fluoro-3-methoxybenzene (14.8 g, 0.062 mol)
.sup.1H NMR (CDCl.sub.3): .delta. 7.20 (m, 1H), 7.10 (dd, 1H), 4.0
(s, 3H).
Other compounds prepared according to the procedure of Example 2
include:
1-Bromo-4-chloro-3-ethoxy-2-fluorobenzene: .sup.1H NMR (CDCl.sub.3)
.delta. 7.20 (m, 1H), 7.10 (dd, 1H), 4.20 (q, 2H), 1.50 (t,
3H).
1-Bromo-2,4-dichloro-3-methoxybenzene: .sup.1H NMR (CDCl.sub.3)
.delta. 7.35 (d, 1H), 7.15 (d, 1H), 3.95 (s, 3H).
1-Chloro-3,5-difluoro-2-methoxybenzene: GC-MS (m/z=178).
3. Preparation of 1-bromo-4-chloro-2-fluoro-5-methoxybenzene
A solution of 4-chloro-2-fluoro-5-methoxyaniline (25.0 g, 0.143
mol) in 10% HBr (250 mL) was cooled to 0.degree. C. and a solution
of sodium nitrite (15.0 g, 0.218 mol) in water (20 mL) was slowly
added. After addition, methylene chloride (50 mL) and cupric
bromide (30.0 g, 0.244 mol) were added slowly. The reaction mixture
was then warmed to ambient temperature, stirred for one hour,
filtered through a bed of celite, and extracted with methylene
chloride (2.times.100 mL). The combined organic phases were dried
and concentrated. Chromatography of the dark oil (5% ethyl acetate
in hexanes) gave 1-bromo-4-chloro-2-fluoro-5-methoxybenzene (16.6
g, 0.070 mol): .sup.1H NMR (CDCl.sub.3): .delta. 7.20 (m, 1H), 7.05
(dd, 1H), 4.00 (s, 3H).
4. Preparation of 1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene
2-Chloro-4,6-difluoroanisole (2.0 g, 11 mmol) was dissolved in 20
mL anhydrous THF and cooled to -70 to -75.degree. C. 2.5M n-Butyl
lithium in hexanes (6.7 mL, 17 mmol) was added dropwise. After
stirring for 75 minutes at -75.degree. C., the mixture was treated
dropwise with a solution of iodine (5.1 g, 20 mmol) in 10 mL THF.
After stirring for 20 minutes, the reaction solution was allowed to
warm to 25.degree. C. over 40 minutes. The reaction mixture was
diluted with Et.sub.2O (50 mL) and stirred with dilute NaHSO.sub.3
solution to destroy excess iodine. The separated aqueous phase was
extracted with 20 mL Et.sub.2O. The combined ether phases were
washed with saturated NaCl, dried, and evaporated to give
1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene (3.1 g, 91% yield):
mp 62-64.degree. C.; GC-MS (m/z=304).
5. Preparation of
1-bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene
A solution of 3-bromo-6-chloro-2-fluorophenol (15.4 g, 0.068 mol)
in dimethylformamide (DMF; 25 mL) was slowly added to a suspension
of sodium hydride (60% dispersion in mineral oil) (4.0 g, 0.10 mol)
in DMF (100 mL) and the reaction mixture was stirred one hour. A
solution of methanesulfonic acid 2,2-difluoroethyl ester (17.5 g,
0.109 mol) in DMF (10 mL) was slowly added. The resulting solution
was heated at 70.degree. C. for eighteen hours. The cooled solution
was diluted with water (200 mL) and extracted with ethyl ether. The
combined organic phases were dried and concentrated. The residual
oil was purified by column chromatography (in hexanes) to give
1-bromo-4-chloro-3-(2,2-difluoroethoxy)-2-fluorobenzene (9.0 g,
0.031 mol): .sup.1H NMR (CDCl.sub.3): .delta. 7.26 (m, 1H), 7.09
(m, 1H), 6.12 (tt, 1H), 4.30 (td, 2H).
6. Preparation of 1-bromo-4-chloro-3-methylthio-2-fluorobenzene
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol)
in THF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL)
at -50.degree. C. After addition, the solution was warmed to
-20.degree. C. and then cooled to -50.degree. C. A solution of
dimethyldisulfide (18.8 g, 0.20 mol) in THF (50 mL) was then slowly
added and the mixture was warmed to ambient temperature. The
reaction was quenched with water (200 mL), extracted with ethyl
acetate (2.times.150 mL), and the combined organic phases dried and
concentrated. The residual red oil was purified by chromatography
(5% ethyl acetate in hexanes) to give
1-bromo-4-chloro-3-methylthio-2-fluorobenzene (23.9 g, 0.094 mol):
.sup.1H NMR (CDCl.sub.3): .delta. 7.40 (m, 1H), 7.15 (dd, 1H), 2.50
(s, 3H).
7. Preparation of 1-bromo-4-chloro-2-fluoro-3-methylbenzene
Diisopropylamine (15.2 g, 150 mmol) was dissolved in 100 mL THF and
the solution was cooled to -50.degree. C. 2.5M n-butyl lithium (50
mL, 125 mmol) was added dropwise by addition funnel and the
solution was again cooled to -50.degree. C.
1-Bromo-4-chloro-3-fluorobenzene (20.95 g, 100 mmol) in 25 mL THF
was then slowly added to the LDA solution at -50.degree. C. keeping
the temperature below -25.degree. C., after which the solution was
allowed to warm to -15.degree. C. The reaction mixture was then
cooled again to -60.degree. C. and iodomethane (9.33 mL, 150 mmol)
was added dropwise. The resulting solution was allowed to warm to
room temperature and concentrated under vacuum. The residue was
partitioned between ethyl acetate and water. The organic phase was
washed with water, dried, and concentrated under vacuum. The
product was purified by column chromatography using hexanes as the
sole solvent to yield 1-bromo-4-chloro-2-fluoro-3-methylbenzene
(19.3 g, 86% yield): .sup.1H NMR (CDCl.sub.3): .delta. 7.30 (m,
1H), 7.05 (dd, 1H), 2.35 (d, 3H).
8. Preparation of 3-bromo-6-chloro-2-fluorobenzaldehyde
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol)
in THF (50 mL) was slowly added to LDA (0.125 mol) in THF (600 mL)
at -50.degree. C. The resulting solution was then warmed to
-20.degree. C. and cooled again to -50.degree. C. A solution of DMF
(14.6 g, 0.20 mol) in THF (50 mL) was slowly added and the reaction
mixture was allowed to warm to room temperature. The reaction was
quenched with water (250 mL) and extracted with ethyl acetate
(2.times.150 mL). The combined organic phases were dried and
concentrated. The product was recrystallized from hexane to give
3-bromo-6-chloro-2-fluorobenzaldehyde (40.0 g, 0.169 mol): mp
92-93.degree. C.
9. Preparation of
1-bromo-4-chloro-2-fluoro-3-difluoromethylbenzene
Diethylamino sulfur trifluoride (15.3 g, 0.096 mol) was added
slowly to a solution of 3-bromo-6-chloro-2-fluorobenzaldehyde (7.50
g, 0.032 mol) in methylene chloride at 0.degree. C. The resulting
solution was stirred for one hour and then allowed to warm to room
temperature. The reaction was carefully quenched with a saturated
solution of sodium bicarbonate in water (100 mL) and extracted with
methylene chloride (2.times.75 mL). The combined organic extracts
were dried and concentrated to give
1-bromo-4-chloro-2-fluoro-3-difluoro-methylbenzene (7.20 g, 0.028
mol): .sup.1H NMR (CDCl.sub.3): .delta. 7.60 (m, 1H), 7.05 (m, 1H),
7.00 (d, 1H).
10. Preparation of 2,4-dichloro-3-methoxyphenylboronic acid
To a solution of 1-bromo-2,4-dichloro-3-methoxybenzene (5.12 g, 20
mmol) in diethyl ether cooled to -70.degree. C. was added 2.5M
n-butyl lithium (8.8 mL, 22 mmol) in portions keeping the
temperature below -60.degree. C. The resulting reaction mixture was
then stirred for 10 minutes before triisopropylborate (6.9 mL, 30
mmol) was added in portions keeping the temperature below
-60.degree. C. The reaction mixture was then allowed to warm to
room temperature and acetyl chloride (60 mmol) was added. The
reaction mixture was stirred for an hour at room temperature and
concentrated. The residue was partitioned between ethyl acetate and
1N NaOH (40 mL) and the organic phase was extracted with additional
1N NaOH (10 mL). The sodium hydroxide extracts were combined, ice
was added, and the solution was acidified to pH 3-4 with
concentrated HCl. The product was then extracted with ethyl acetate
and the organic phase was dried and concentrated to yield
2,4-dichloro-3-methoxyphenylboronic acid (3.27 g, 14.8 mmol):
.sup.1H NMR (CDCl.sub.3): .delta. 8.44 (br s, 2H), 7.42 (d, 1H),
7.15 (d, 1H), 3.8 (s, 3H).
Other boronic acids prepared according to the procedure of Example
10 include:
4-Chloro-2-fluoro-3-methylthiophenylboronic acid: .sup.1H NMR
(CDCl.sub.3): .delta. 8.39 (br s, 2H), 7.49 (m, 1H), 7.35 (m, 1H),
2.43 (s, 3H).
4-Chloro-2-fluoro-3-methylphenylboronic acid: .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.27 (br s, 2H), 7.5-7.2 (m, 2H), 2.25 (m,
3H).
4-Chloro-3-(2,2-difluoroethoxy)-2-fluorophenylboronic acid: .sup.1H
NMR (DMSO-d.sub.6): .delta. 8.38 (br s, 2H), 7.52 (m, 1H), 7.29 (M,
1H), 6.33 (tt, 1H), 4.32 (m, 2H).
11. Preparation of
2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane
To a solution of 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (10.4
g, 0.043 mol) in diethyl ether (150 mL) at -78.degree. C. was
slowly added n-butyl lithium (2.5M, 19.0 mL, 0.0475 mol), and the
solution was stirred for thirty minutes. A solution of triisopropyl
borate (12.0 g, 0.064 mL) in THF (25 mL) was slowly added and the
solution warmed to 0.degree. C. Acetyl chloride (10.0 g, 0.13 mol)
was added. After stiffing for one hour the solution was
concentrated and the solid residue was partitioned between ethyl
acetate (150 mL) and 1N sodium hydroxide (50 mL). Ice was added to
the aqueous phase that was subsequently acidified with sufficient
concentrated hydrochloric acid to obtain a pH of 2. The
heterogeneous mixture was extracted with ethyl acetate (2.times.150
mL) and the combined organic phases were dried and concentrated.
The resulting solid was slurried in toluene, propane-1,3-diol (6.6
g, 0.09 mol) was added, and the resulting mixture was heated under
reflux to remove water via a Dean-Stark trap. After two hours, the
mixture was allowed to cool and was concentrated under vacuum. The
resulting oil was dissolved in methylene chloride (50 mL), washed
with water (25 mL), dried, and concentrated to give
2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (6.4 g,
0.062 mol): .sup.1H NMR (CDCl.sub.3): .delta. 7.15 (m, 1H), 6.95
(dd, 1H), 4.05 (t, 4H), 3.8 (s, 3H), 1.95 (t, 2H).
Other compounds prepared according to the procedure of Example 11
include:
2-(4-Chloro-2-fluoro-5-methoxyphenyl)-[1,3,2]-dioxaborinane:
.sup.1H NMR (CDCl.sub.3): .delta. 7.25 (d, 1H), 7.05 (d, 1H), 4.20
(t, 4H), 4.15 (s, 3H), 2.10 (t, 2H).
2-(4-Chloro-2-fluoro-3-difluoromethylphenyl)-[1,3,2]-dioxaborinane
.sup.1H NMR (CDCl.sub.3): .delta. 7.75 (m, 1H), 7.15 (dd, 1H),
6.90-7.15 (t, 1H) 4.20 (t, 4H), 2.05 (t, 2H).
12. Preparation of
(4-chloro-3-ethoxy-2-fluorophenyl)trimethylstannane
1-Bromo-4-chloro-3-ethoxy-2-fluorobenzene: (3.55 g, 14 mmol) and
hexamethylditin (5.9 g, 18 mmol) were dissolved in 25 mL p-dioxane
and bis(triphenylphosphine)palladium(II)dichloride (491 mg, 0.70
mmol) was added. The reaction mixture was heated at 100.degree. C.
for 5 hours, allowed to cool to room temperature and concentrated.
The residue was purified by column chromatography (0-5% ethyl
acetate/hexane gradient) to yield
(4-chloro-3-ethoxy-2-fluorophenyl)trimethylstannane (4.3 g, 12.7
mmol); 85% pure by GC-MS m/z 338 (M.sup.+).
13. Preparation of 1-fluoro-2,3-methylenedioxybenzene
Alliquat 336 (methyltrioctylammonium chloride (0.63 g, 0.0016 mol),
dibromomethane (40.7 g, 234.2 mmol), and water (31 mL) were placed
in a 500 mL 3-necked flask equipped with an addition funnel,
condenser and a stir bar. The addition funnel was charged with a
solution of 3-fluorocatechol (20.0 g, 6.1 mmol) in 5M sodium
hydroxide (80 mL). The mixture in the flask was heated to reflux
and the solution of the catechol was added dropwise with good
stiffing over 1.5 hours. The resulting dark mixture was heated an
additional 2 hours at reflux. After cooling to room temperature,
the reaction was diluted with methylene chloride and water. The
aqueous layer was extracted with methylene chloride and the
combined organic layers were dried and concentrated to give
1-fluoro-2,3-methylenedioxybenzene (14.6 g, 104.2 mmol) as a dark
yellow oil: .sup.1H NMR (CDCl.sub.3): .delta. 6.80 (m, 1H), 6.68
(m, 2H), 6.04 (s, 2H).
14. Preparation of 2-fluoro-3,4-methylenedioxyphenylboronic
acid
1-Fluoro-2,3-methylenedioxybenzene (5.0 g, 35.7 mmol) was dissolved
in THF (70 mL) and the solution was cooled to -65.degree. C. in a
dry ice acetone bath. n-Butyl lithium (2.5 g, 15.7 mL, 39.3 mmol)
was added to the solution via syringe with stiffing. The reaction
was allowed to warm to -35.degree. C. over 1 hour, then cooled to
-65.degree. C. and treated with trimethylborate (4.1 g, 39.3 mmol)
via syringe. The reaction was allowed to warm slowly to room
temperature, quenched with 1N HCl (50 mL), stirred for 15 minutes,
and then extracted with ether. The organic phase was then extracted
with 1N sodium hydroxide and this aqueous extract was then
acidified with 1N hydrochloric acid. The acidic aqueous solution
was then extracted with two portions of ether and these combined
ether extracts were dried and concentrated to an oily solid that
was triturated with methylene chloride. The resulting solid was
collected by filtration, washed with methylene chloride, and dried
to give 1-fluoro-2,3-methylenedioxyphenylboronic acid (1.4 g, 7.6
mmol) as a tan solid: .sup.1H NMR (DMSO-d.sub.6): .delta. 8.05 (br
s, 2H), 7.08 (dd, 1H, J=7.8, 5.1 Hz), 6.76 (d, 1H, J=7.8 Hz), 6.08
(s, 2H).
15. Preparation of 3-bromo-6-chloro-2-fluorobenzonitrile
A suspension of 3-bromo-6-chloro-2-fluorobenzaldehyde (9.0 g, 0.04
mol) and hydroxylamine-O-sulfonic acid (7.50 g, 0.07 mole) in water
(300 mL) was heated at 50.degree. C. for eighteen hours. The
suspension was cooled and the solid was collected to give
3-bromo-6-chloro-2-fluorobenzonitrile (8.8 g, 0.04 mol): .sup.1H
NMR (CDCl.sub.3): .delta. 7.75 (m, 1H), 7.25 (m, 1H).
16. Preparation of 3-bromo-2-fluoro-6-chlorobenzamide
Concentrated sulfuric acid (15 mL) was placed in a 100 mL 3-neck
flask equipped with an internal thermometer and heated to
55.degree. C. 3-Bromo-2-fluoro-6-chlorobenzonitrile (11.0 g, 47
mmol) was added portion-wise to the acid with stiffing maintaining
the temperature above 50.degree. C. The dark solution was heated at
65.degree. C. for 24 hours, allowed to cool to room temperature,
poured over ice, and cautiously neutralized with concentrated
ammonium hydroxide. The mixture was extracted with two portions of
ethyl acetate and the combined organic layers were dried and
concentrated to give 3-bromo-2-fluoro-6-chlorobenzamide (11.5 g,
45.5 mmol) as a light orange solid: mp 157-158.degree. C., .sup.1H
NMR (CDCl.sub.3): .delta. 7.54 (t, 1H), 7.14 (dd, 1H), 6.03 (br s,
1H) 5.81 (br s, 1H).
17. Preparation of 3-bromo-6-chloro-2-fluoroaniline
Sodium hydroxide (4 g, 100.0 mmol) was dissolved in water (70 mL)
and the resulting solution was cooled in an ice bath and treated
with bromine (4.7 g, 29.7 mmol). Solid
3-bromo-2-fluoro-6-chlorobenzenecarboxamide (5.0 g, 19.9 mmol) was
added slowly with good stirring and the orange mixture was heated
to reflux for 2 hours. The cooled reaction mixture was extracted
with methylene chloride and the organic phase was dried and
concentrated. Recrystallization of the product from cold hexanes
gave 3-bromo-6-chloro-2-fluoroaniline (2.8 g, 12.6 mmol) as an off
white solid: mp 61-62.degree. C.: .sup.1H NMR (CDCl.sub.3): .delta.
6.94 (dd, 1H), 6.83 (dd, 1H), 4.16 (br s, 2H).
18. Preparation of
N-(3-bromo-6-chloro-2-fluorophenyl)-N,N-dimethylamine
3-Bromo-6-chloro-2-fluoroaniline (2.5 g, 11.1 mmol) was dissolved
in THF (25 mL) and treated with 37% formaldehyde (0.84 g, 2.1 mL,
27.8 mmol), dibutyltindichloride (0.07 g, 0.22 mmol), and phenyl
silane (1.33 g, 12.3 mmol). The resulting solution was then stirred
at room temperature under nitrogen for 48 hours. The reaction
mixture was concentrated under vacuum and purified by column
chromatography (hexanes) to give
N-(3-bromo-6-chloro-2-fluorophenyl)-N,N-dimethylamine (2.0 g, 7.9
mmol) as an oil: .sup.1H NMR (CDCl.sub.3): .delta. 7.19 (dd, 1H),
7.04 (dd, 1H), 2.88 (s, 3H), 2.87 (s, 3H).
19. Preparation of 4-chloro-3-(dimethylamino)-2-fluorophenylboronic
acid
N-(3-Bromo-6-chloro-2-fluorophenyl)-N,N-dimethylaniline (0.88 g 3.5
mmol) was dissolved in ether (10 mL) and cooled to -60.degree. C.
under nitrogen. n-Butyl lithium (0.23 g, 3.6 mmol, 1.45 mL of a
2.5M solution) was added dropwise via syringe keeping the
temperature under -55.degree. C. After 0.5 hours, trimethylborate
(0.40 g, 0.38 mmol) was added via syringe and the reaction was
allowed to warm to room temperature. 1N HCl (3.5 mL) was added and
the mixture was stirred for 0.5 hours. The mixture was diluted with
water and extracted with ether. The organic phase was dried and
concentrated to give 0.75 g of a foam that was triturated with
hexanes. The resulting solid was collected by filtration and dried
to give 4-chloro-3-(dimethylamino)-2-fluorophenylboronic acid (0.5
g, 2.3 mmol) as an off-white solid. .sup.1H NMR (DMSO-d.sub.6)
revealed the solid to be a mixture of what appears to be the
boronic acid and anhydrides. The solid was subsequently used
without further purification or characterization.
20. Preparation of 2,6-dibromo-5-chloropyrimidine-4-carboxylic acid
methyl ester
Methyl 5-chloroorotate (33.8 g, 165 mmol, see H. Gershon, J. Org.
Chem. 1962, 27, 3507-3510 for preparation) and phosphorous
oxybromide (100 g, 349 mmol) were combined in sulfolane (200 mL).
The resulting suspension was heated at 100-110.degree. C. for 2
hours and then allowed to cool to room temperature. The cooled
reaction mixture was poured onto ice and the product was extracted
with hexane (4.times.150 mL). The organic extracts were combined
and concentrated to yield
2,6-dibromo-5-chloropyrimidine-4-carboxylic acid methyl ester (32.0
g, 58.7% yield) that was used in subsequent reactions without
further purification. An analytical sample was recrystallized from
heptane: mp 92-93.degree. C.
21. Preparation of
2-bromo-5-chloro-6-methylthiopyrimidine-4-carboxylic acid methyl
ester
An aqueous solution (15 mL) of sodium thiomethoxide (1.37 g, 19.5
mmol) was added dropwise to a solution of
2,6-dibromo-5-chloro-pyrimidine-4-carboxylic acid methyl ester
(4.96 g, 15 mmol) in benzene (100 mL). The biphasic solution was
stirred at room temperature for two hours at which point GC
analysis indicated complete consumption of starting material. The
organic phase was washed with brine twice, dried, and concentrated.
Purification by column chromatography yielded
2-bromo-5-chloro-6-methylthiopyrimidine-4-carboxylic acid methyl
ester (4.2 g, 94% yield): mp 105-106.degree. C.
22. Preparation of
5-chloro-6-methylthio-2-trimethylstannanylpyrimidine-4-carboxylic
acid methyl ester
Hexamethylditin (5.0 g, 15.3 mmol),
bis(triphenylphosphine)-palladium(II)dichloride (448 mg, 0.64
mmol), and 2-bromo-5-chloro-6-methylthiopyrimidine-4-carboxylic
acid methyl ester (3.8 g, 12.75 mmol) were combined in dioxane and
heated at 100.degree. C. for 3 hours. The reaction mixture was then
allowed to cool to room temperature, concentrated, and the product
was isolated by column chromatography (Note: To avoid decomposition
of product, column must be completed rapidly). This process yielded
5-chloro-6-methylthio-2-trimethylstannanylpyrimidine-4-carboxylic
acid methyl ester as a clear oil product (2.0 g, 41% yield):
.sup.1H NMR (CDCl.sub.3): .delta. 3.98 (s, 3H), 2.58 (s, 3H), 0.39
(s, 9H).
23. Preparation of 6-amino-2,5-dichloropyrimidine-4-carboxylic acid
methyl ester
Ammonia was bubbled through a solution of
2,5,6-trichloro-pyrimidine-4-carboxylic acid methyl ester (15.94 g,
66 mmol, see H. Gershon, J. Org. Chem. 1962, 27, 3507-3510 for
preparation) in p-dioxane (150 mL) for 30 minutes. The solvent was
then removed and the residue partitioned between ethyl acetate and
water. The organic phase was dried and concentrated under vacuum.
The product was purified by column chromatography to provide
6-amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester
(12.74 g, 87% yield): mp 164-166.degree. C.
24. Preparation of 2-chloro-6-methylthiopyrimidine-4-carboxylic
acid methyl ester
An aqueous solution (45 mL) of sodium thiomethoxide (4.7 g, 67
mmol) was added dropwise to a solution of
2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (12.5 g,
60.4 mmol) in benzene (300 mL). The biphasic solution was stirred
at room temperature for two hours at which point GC analysis
indicated complete consumption of starting material. The organic
phase was washed with brine twice, dried, and concentrated.
Purification by column chromatography yielded
2-chloro-6-methylthiopyrimidine-4-carboxylic acid methyl ester (5.6
g, 42.6% yield): mp 90-92.degree. C.; .sup.1H NMR (CDCl.sub.3):
.delta. 7.78 (s, 1H), 4.00 (s, 3H), 2.63 (s, 3H).
25. Preparation of
2-chloro-6-methanesulfonylpyrimidine-4-carboxylic acid methyl
ester
2-Chloro-6-methylthiopyrimidine-4-carboxylic acid methyl ester
(4.38 g, 20 mmol) was dissolved in methylene chloride and
m-chloroperoxy-benzoic acid (MCPBA; 70%) (12.3 g, 50 mmol) was
added. The reaction mixture was stirred at room temperature for 3
days, concentrated under vacuum, and the residue partitioned
between ethyl acetate and water. The organic phase was washed with
a sodium bisulfite solution, washed with a sodium bicarbonate
solution, dried, and concentrated under vacuum. The product was
purified by column chromatography (methylene chloride/ethyl acetate
gradient) to yield
2-chloro-6-methanesulfonylpyrimidine-4-carboxylic acid methyl ester
(3.8 g, 76% yield): mp 127-129.degree. C.: .sup.1H NMR
(CDCl.sub.3): .delta. 8.56 (s, 1H), 4.09 (s, 3H), 3.34 (s, 3H).
26. Preparation of 6-amino-2-chloropyrimidine-4-carboxylic acid
methyl ester
2-Chloro-6-methanesulfonylpyrimidine-4-carboxylic acid methyl ester
(3.7 g, 14.75 mmol) was dissolved in dioxane and 7N ammonia in
methanol was added. The reaction mixture was stirred at room
temperature for 3 hours, concentrated under vacuum, and the residue
partitioned between ethyl acetate and water. The organic phase was
dried and concentrated. The product was purified by column
chromatography to provide 6-amino-2-chloropyrimidine-4-carboxylic
acid methyl ester (2.35 g, 85% yield): .sup.1H NMR (DMSO-d.sub.6):
.delta. 7.6 (br s, 1H), 7.00 (s, 1H), 3.84 (s, 3H), 3.33 (s,
3H).
27. Preparation of
5-chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-6-methane-sulfonylpyrimidin-
e-4-carboxylic acid methyl ester
2-Bromo-5-chloro-6-methylthiopyrimidine-4-carboxylic acid methyl
ester (2.98 g, 10 mmol),
(4-chloro-3-ethoxy-2-fluorophenyl)-trimethylstannane (3.37 g, 10
mmol), and bis(triphenylphosphine)palladium(II)dichloride (351 mg,
0.5 mmol) were combined in 20 mL N-methylpyrrolidinone and heated
at 110.degree. C. for 3 hours. The reaction mixture was allowed to
cool to room temperature and was then diluted with water. The water
was decanted from the sticky residue and the residue was washed
with additional water. The residue was purified by column
chromatography (ethyl acetate/hexane gradient) and the intermediate
product was combined with 2.5 eq of MCPBA in methylene chloride and
stirred overnight. The excess MCPBA was quenched by the addition of
a sodium bisulfite solution and the product was extracted with
diethyl ether. The organic phase was washed with sodium bicarbonate
solution, concentrated, and purified by column chromatography
(ethyl acetate/hexane gradient). A second purification by column
chromatography (methylene chloride only) yielded
5-chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-6-methanesulfonylpyrimidine-
-4-carboxylic acid methyl ester (350 mg, 8.3% yield): mp
164-166.degree. C.
28. Preparation of
6-amino-5-chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-pyrimidine-4-carbox-
ylic acid methyl ester (Compound 1)
5-Chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-6-methane-sulfonylpyrimidin-
e-4-carboxylic acid methyl ester (350 mg, 0.83 mmol) was dissolved
in 10 mL p-dioxane and 7N ammonia in methanol (0.43 mL, 3 mmol) was
added. The reaction mixture was stirred at room temperature for 3
hours and then concentrated. The residue was partitioned between
ethyl acetate and water and the organic phase was dried and
concentrated. The product was purified by column chromatography to
yield
6-amino-5-chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-pyrimidine-4-carbox-
ylic acid methyl ester (160 mg, 54% yield): .sup.1H NMR
(CDCl.sub.3): .delta. 7.65 (dd, 1H), 7.24 (dd, 1H), 5.67 (br s,
2H), 4.22 (q, 2H), 4.03 (s, 3H), 1.46 (t, 3H).
29. Preparation of
5-chloro-2-(4-chloro-2,6-difluoro-3-methoxyphenyl)-6-methylthiopyrimidine-
-4-carboxylic acid methyl ester
5-Chloro-6-methylthio-2-trimethylstannanylpyrimidine-4-carboxylic
acid methyl ester (500 mg, 1.3 mmol),
1-chloro-3,5-difluoro-4-iodo-2-methoxybenzene (475 mg, 1.6 mmol)
and Pd[P(o-Tol).sub.3]Cl.sub.2 (100 mg, 0.13 mmol) were combined in
3 mL deaerated 1,2-dichloroethane. The resulting solution was
heated at 130.degree. C. for 20 minutes in a CEM Discover
microwave. This process was repeated with another 500 mg sample of
the stannane. The solvent was removed from the combined reaction
mixtures and the residue was chromatographed on a 50 mm.times.250
mm YMC AQ column using 75% acetonitrile-25% 0.1% v/v
H.sub.3PO.sub.4 to yield
5-chloro-2-(4-chloro-2,6-difluoro-3-methoxyphenyl)-6-methylthio-pyrimidin-
e-4-carboxylic acid methyl ester (153 mg, 15% yield): mp
144-146.degree. C.; MS: m/z=394.
30. Preparation of
6-amino-5-chloro-2-(4-chloro-2,6-difluoro-3-methoxy-phenyl)pyrimidine-4-c-
arboxylic acid methyl ester (Compound 2)
5-chloro-2-(4-chloro-2,6-difluoro-3-methoxyphenyl)-6-methylthiopyrimidine-
-4-carboxylic acid methyl ester (150 mg, 0.38 mmol) was dissolved
in 10 mL methylene chloride and treated with 70% MCPBA (240 mg,
0.95 mmol). After stiffing for 2 hours an additional 100 mg of
MCPBA was added and stirring was continued for 18 hours. The
mixture was stirred with 5 mL 10% NaHSO.sub.3 solution for 20
minutes. The separated organic phase was washed with 10%
NaHCO.sub.3 solution (5 mL), washed with water (5 mL), dried, and
concentrated. The residue was dissolved in 10 mL 0.5M ammonia in
dioxane and stirred at 25.degree. C. for 20 hours and then
concentrated under vacuum. The residue was taken up in 10 mL ethyl
acetate, washed with 10 mL of water, washed with 5 mL of brine,
dried, and concentrated to give
6-amino-5-chloro-2-(4-chloro-2,6-difluoro-3-methoxyphenyl)pyrimidine-4-ca-
rboxylic acid methyl ester (51 mg, 37% yield): .sup.1H NMR
(CDCl.sub.3): .delta. 7.03 (dd, 1H), 5.87 (br s, 2H), 4.0 (s, 3H),
3.93 (d, 3H).
31. Preparation of
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carbo-
xylic acid methyl ester (Compound 3)
6-Amino-2,5-dichloropyrimidine-4-carboxylic acid methyl ester (888
mg, 4 mmol),
2-(4-chloro-2-fluoro-3-methoxyphenyl)-[1,3,2]-dioxaborinane (1.47
g, 6 mmol), bis(triphenylphosphine)palladium(II)dichloride (280 mg,
0.4 mmol), and cesium fluoride (1.21 g, 8 mmol) were combined in 8
mL of 1,2-dimethoxyethane and 8 mL of water. The reaction mixture
was heated at 80.degree. C. for 3 hours and the cooled reaction
mixture was partitioned between ethyl acetate and water. The
organic phase was washed with water, dried, and concentrated. The
product was purified by column chromatography (ethyl acetate/hexane
gradient) then purified again by column chromatography (methylene
chloride/ethyl acetate gradient) to yield
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4--
carboxylic acid methyl ester (738 mg, 53.5% yield):
.sup.1H NMR (CDCl.sub.3): .delta. 7.64 (dd, 1H), 7.22 (dd, 1H),
5.64 (br s, 2H), 4.01 (s, 3H), 3.99 (d, 3H).
The following compounds were prepared according to the procedure of
Example 31 utilizing either boronic acid esters or boronic
acids:
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methylthiophenyl)pyrimidine-4-car-
boxylic acid methyl ester (Compound 4): .sup.1H NMR (CDCl.sub.3):
.delta. 7.83 (dd, 1H), 7.33 (dd, 1H), 5.71 (br s, 2H), 4.01 (s,
3H), 2.5 (d, 3H).
6-Amino-5-chloro-2-(4-chloro-2-fluoro-5-methoxyphenyl)pyrimidine-4-carbox-
ylic acid methyl ester (Compound 5): .sup.1H NMR (CDCl.sub.3):
.delta. 7.53 (d, 1H), 7.22 (d, 1H), 5.71 (br s, 2H), 4.02 (s, 3H),
3.95 (s, 3H).
6-Amino-5-chloro-2-(2,4-dichloro-3-methoxyphenyl)pyrimidine-4-carboxylic
acid methyl ester (Compound 6): .sup.1H NMR (CDCl.sub.3): .delta.
7.39 (m, 2H), 5.71 (br s, 2H), 4.02 (s, 3H), 3.95 (s, 3H).
6-Amino-5-chloro-2-(4-chloro-3-difluoromethyl-2-fluorophenyl)pyrimidine-4-
-carboxylic acid methyl ester (Compound 7): mp 155-157.degree.
C.
6-Amino-5-chloro-2-(4-chloro-3-dimethylamino-2-fluorophenyl)pyrimidine-4--
carboxylic acid methyl ester (Compound 8): mp 143-144.degree.
C.
6-Amino-5-chloro-2-(4-fluorobenzo[1,3]dioxol-5-yl)pyrimidine-4-carboxylic
acid methyl ester (Compound 9): .sup.1H NMR (CDCl.sub.3): .delta.
7.59 (dd, 1H), 6.72 (dd, 1H), 6.08 (s, 2H), 5.6 (br s, 2H), 4.03
(s, 3H).
6-Amino-5-chloro-2-[4-chloro-3-(2,2-difluoroethoxy)-2-fluorophenyl]-pyrim-
idine-4-carboxylic acid methyl ester (Compound 10): mp
139-141.degree. C.
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methylphenyl)pyrimidine-4-carboxy-
lic acid methyl ester (Compound 11): mp 166-168.degree. C.
32. Preparation of
6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyrimidine-4-carboxylic
acid methyl ester
6-Amino-2-chloro-pyrimidine-4-carboxylic acid methyl ester (2.25 g,
12 mmol), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (3.27 g, 16
mmol), and bis(triphenylphosphine)palladium(II)dichloride (842 mg,
1.2 mmol) were combined in 12 mL of dimethoxyethane and 12 mL of
water. The reaction mixture was heated at 80.degree. C. for 2 hours
and the cooled reaction mixture was partitioned between ethyl
acetate and water. The organic phase was washed with water, dried,
and concentrated under vacuum. The product was purified by column
chromatography to yield
6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)pyrimidine-4-carboxylic
acid methyl ester (2.0 g, 53.5% yield): mp 188-190.degree. C.:
.sup.1H NMR (CDCl.sub.3): .delta. 7.66 (dd, 1H), 7.22 (dd, 1H),
7.14 (s, 1H), 5.25 (br s, 2H), 4.0 (s, 3H), 3.99 (s, 3H).
33. Preparation of
6-amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-5-fluoro-pyrimidine-4-carb-
oxylic acid methyl ester (Compound 12)
6-Amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyrimidine-4-carboxylic
acid methyl ester (778 mg, 2.5 mmol) and F-TEDA (974 mg, 2.75 mmol)
were combined in acetonitrile and heated at reflux for 4 hours
(reaction made little progress after 1 hour). The reaction mixture
was cooled to room temperature and filtered. The filtrate was
concentrated, purified by column chromatography, and then purified
a second time by preparative HPLC to yield
6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropyrimidine-4-carbox-
ylic acid methyl ester (26 mg, 3.2% yield): mp 200-202.degree. C.:
.sup.1H NMR (CDCl.sub.3): .delta. 7.62 (dd, 1H), 7.21 (dd, 1H),
5.40 (br s, 2H), 4.02 (s, 3H), 4.0 (d, 3H)
34. Preparation of
6-amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carbox-
ylic acid methyl ester (Compound 13)
6-Amino-2-(4-chloro-2-fluoro-3-methoxy-phenyl)-pyrimidine-4-carboxylic
acid methyl ester (778 mg, 2.5 mmol) and N-bromosuccinimide (489
mg, 2.75 mmol) were combined in chloroform and heated at reflux for
12 hours. The cooled reaction mixture was concentrated and the
product was isolated by column chromatography to yield
6-amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxy-
lic acid methyl ester (752 mg, 77% yield): mp 173-175.degree. C.:
.sup.1H NMR (CDCl.sub.3): .delta. 7.66 (dd, 1H), 7.24 (dd, 1H),
5.73 (br s, 2H), 4.03 (s, 3H), 4.01 (d, 3H).
35. Preparation of
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methanesulfinyl-phenyl)pyrimidine-
-4-carboxylic acid methyl ester
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methylthio-phenyl)pyrimidine-4-ca-
rboxylic acid methyl ester (2.4 g, 6.63 mmol) was dissolved with
heating in a minimum amount of trifluoroethanol (50 mL). After
allowing the reaction mixture to cool to room temperature, 30%
hydrogen peroxide (3.0 mL, 26.5 mmol) was added and the reaction
mixture was stirred for 2 days. An aqueous solution of sodium
sulfite (10% solution) was added to quench excess oxidant (exotherm
noted) and the reaction mixture was stirred for 1 hour. Additional
water was then added and the reaction mixture was filtered. The
precipitate was found to be pure
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methanesulfinylphenyl)pyrimidine--
4-carboxylic acid methyl ester (2.13 g, 85% yield): mp
256-258.degree. C.: .sup.1H NMR (CDCl.sub.3): .delta. 8.03 (dd,
1H), 7.54 (dd, 1H), 3.92 (s, 3H), 3.13 (s, 3H).
36. Preparation of
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-trifluoro-methylthiophenyl)pyrimi-
dine-4-carboxylic acid methyl ester (Compound 14)
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methanesulfinyl-phenyl)pyrimidine-
-4-carboxylic acid methyl ester (378 mg, 1 mmol) was suspended in
trifluoroacetic anhydride (5 mL) and the reaction mixture was
heated at 60.degree. C. in a sealed tube for 3 hours. The reaction
mixture was allowed to cool to room temperature and the excess
trifluoroacetic anhydride was removed under reduced pressure. To
the residue was added 40 mL of a 1:1 mixture of triethylamine and
methanol that was cooled to 0.degree. C. The reaction mixture was
immediately concentrated under vacuum and the resulting product
redissolved in acetonitrile. To this solution was added
trifluoromethyliodide (1.96 g, 10 mmol) condensed with a cold
finger. The reaction mixture was placed in a glass sealed reaction
vessel and irradiated with UV light for 15 minutes. The reaction
mixture was then concentrated under vacuum and the residue was
stirred in methanol overnight to remove the amine protecting group.
The reaction mixture was concentrated once more and purified by
column chromatography to yield
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-trifluoromethylthiopheny-
l)pyrimidine-4-carboxylic acid methyl ester (238 mg, 57% yield): mp
167-169.degree. C.: .sup.1H NMR (CDCl.sub.3): .delta. 8.13 (dd,
1H), 7.47 (dd, 1H), 5.69 (br s, 2H), 4.02 (s, 3H).
37. Preparation of
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carbo-
xylic acid (Compound 15)
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carbo-
xylic acid methyl ester (156 mg, 0.45 mmol) was dissolved in 15 mL
methanol and 1 mL of 2N sodium hydroxide (2 mmol) was added. The
reaction mixture was stirred at room temperature for 2 hours and
then acidified with a slight excess of 2N HCl. The resulting
solution was concentrated under a nitrogen stream and several crops
of crystals were collected during this process yielding
6-amino-5-chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carbox-
ylic acid (100 mg, 66.7% yield): mp 172-173.degree. C.: .sup.1H NMR
(DMSO-d.sub.6): .delta. 8.0 (br, 1H), 7.63 (dd, 1H), 7.43 (dd, 1H),
3.92 (s, 3H).
Other compounds prepared by the method of Example 37 include:
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methylthiophenyl)pyrimidine-4-car-
boxylic acid (Compound 16): mp 139-141.degree. C.
6-Amino-5-chloro-2-(4-chloro-2-fluoro-5-methoxyphenyl)pyrimidine-4-10
carboxylic acid (Compound 17): mp 202-204.degree. C.
6-Amino-5-chloro-2-(2,4-dichloro-3-methoxyphenyl)pyrimidine-4-carboxylic
acid (Compound 18): 139-141.degree. C.
6-Amino-5-chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)pyrimidine-4-carboxy-
lic acid (Compound 19): mp 132-134.degree. C.
6-Amino-5-chloro-2-(4-chloro-2-fluoro-3-methylphenyl)pyrimidine-4-carboxy-
lic acid (Compound 20): mp 210-212.degree. C.
6-Amino-5-chloro-2-[4-chloro-3-(2,2-difluoroethoxy)-2-fluorophenyl]-pyrim-
idine-4-carboxylic acid (Compound 21): .sup.1H NMR
(DMSO-d.sub.6+D.sub.2O): .delta. 7.7 (dd, 1H), 7.46 (dd, 1H), 6.34
(tt, 1H), 4.41 (td, 2H).
6-Amino-5-chloro-2-(4-fluoro-benzo[1,3]-dioxol-5-yl)pyrimidine-4-carboxyl-
ic acid (Compound 22): .sup.1H NMR (DMSO-d.sub.6+D.sub.2O): .delta.
7.48 (dd, 1H), 6.91 (d, 1H), 8.2 (s, 2H).
6-Amino-5-chloro-2-(4-chloro-3-dimethylamino-2-fluorophenyl)pyrimidine-4--
carboxylic acid (Compound 23): mp 181-183.degree. C.
6-Amino-5-chloro-2-(4-chloro-3-difluoromethyl-2-fluorophenyl)pyrimidine-4-
-carboxylic acid (Compound 24): mp 166-168.degree. C.
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)pyrimidine-4-carboxy-
lic acid (Compound 25) mp 173-175.degree. C.
38. Preparation of Herbicidal Compositions
In the following illustrative compositions, parts and percentages
are by weight.
Emulsifiable Concentrates
Formulation A
TABLE-US-00001 WT % Compound 1 26.2 Polyglycol 26-3 5.2 Nonionic
emulsifier-(di-sec-butyl)- phenyl-poly(oxypropylene)block polymer
with (oxyethylene). The polyoxyethelene content is about 12 moles.
Witconate P12-20 (Anionic emulsifier- 5.2 calcium dodecylbenzene
sulfonate- 60 wt. % active) Aromatic 100 (Xylene range aromatic
63.4 solvent)
Formulation B
TABLE-US-00002 WT % Compound 3 3.5 Sunspray 11N (paraffin oil) 40.0
Polyglycol 26-3 19.0 Oleic acid 1.0 Xylene range aromatic solvent
36.5
Formulation C
TABLE-US-00003 WT % Compound 6 13.2 Stepon C-65 25.7 Ethomeen T/25
7.7 Ethomeen T/15 18.0 Xylene range aromatic solvent 35.4
Formulation D
TABLE-US-00004 WT % Compound 2 30.0 Agrimer Al-10LC (emulsifier)
3.0 N-methyl-2-pyrrolidone 67.0
Formulation E
TABLE-US-00005 WT % Compound 4 10.0 Agrimul 70-A (dispersant) 2.0
Amsul DMAP 60 (thickener) 2.0 Emulsogen M (emulsifier) 8.0 Attagel
50 (suspension aid) 2.0 Crop oil 76.0
These concentrates can be diluted with water to give emulsions of
suitable concentrations for controlling weeds.
Wettable Powders
Formulation F
TABLE-US-00006 WT % Compound 15 26.0 Polyglycol 26-3 2.0 Polyfon H
4.0 Zeosyl 100 (Precipitated hydrated SiO.sub.2) 17.0 Barden clay +
inerts 51.0
Formulation G
TABLE-US-00007 WT % Compound 19 62.4 Polyfon H (sodium salt of
lignin 6.0 sulfonate) Sellogen HR (sodium naphthalene 4.0
sulfonate) Zeosyl 100 27.6
Formulation H
TABLE-US-00008 WT % Compound 21 1.4 Kunigel V1 (carrier) 30.0
Stepanol ME Dry (wetter) 2.0 Tosnanon GR 31A (binder) 2.0 Kaolin
NK-300 Clay (filler) 64.6
The active ingredient is applied to the corresponding carriers and
then these are mixed and ground to yield wettable powders of
excellent wettability and suspension power. By diluting these
wettable powders with water it is possible to obtain suspensions of
suitable concentrations for controlling weeds.
Water Dispersible Granules
Formulation I
TABLE-US-00009 WT % Compound 25 26.0 Sellogen HR 4.0 Polyfon H 5.0
Zeosyl 100 17.0 Kaolinite clay 48.0
The active ingredient is added to the hydrated silica, which is
then mixed with the other ingredients and ground to a powder. The
powder is agglomerated with water and sieved to provide granules in
the range of -10 to +60 mesh. By dispersing these granules in water
it is possible to obtain suspensions of suitable concentrations for
controlling weeds.
Granules
Formulation J
TABLE-US-00010 WT % Compound 20 5.0 Celetom MP-88 95.0
The active ingredient is applied in a polar solvent such as
N-methylpyrollidinone, cyclohexanone, gamma-butyrolactone, etc. to
the Celetom MP 88 carrier or to other suitable carriers. The
resulting granules can be applied by hand, granule applicator,
airplane, etc. in order to control weeds.
Formulation K
TABLE-US-00011 WT % Compound 18 1.0 Polyfon H 8.0 Nekal BA 77 2.0
Zinc Stearate 2.0 Barden Clay 87.0
All materials are blended and ground to a powder then water is
added and the clay mixture is stirred until a paste is formed. The
mixture is extruded through a die to provide granules of proper
size.
Water Soluble Liquids
Formulation L
TABLE-US-00012 WT % Compound 23 3.67 Monoethanolamine pH buffer 0.5
Water 95.83
The active ingredient is dissolved in an appropriate amount of
water and the additional monoethanolamine is added as a buffer. A
water-soluble surfactant may be added. Other aids may be
incorporated to improve physical, chemical and/or formulation
properties.
39. Evaluation of General Postemergence Herbicidal Activity
Seeds or nutlets of the desired test plant species were planted in
Sun Gro MetroMix.RTM. 306 planting mixture, which typically has a
pH of 6.0 to 6.8 and an organic matter content of about 30 percent,
in plastic pots with a surface area of 64 square centimeters. When
required to ensure good germination and healthy plants, a fungicide
treatment and/or other chemical or physical treatment was applied.
The plants were grown for 7-21 days in a greenhouse with an
approximate 15 hour photoperiod which was maintained at about
23-29.degree. C. during the day and 22-28.degree. C. during the
night. Nutrients and water were added on a regular basis and
supplemental lighting was provided with overhead metal halide
1000-Watt lamps as necessary. The plants were employed for testing
when they reached the first or second true leaf stage.
A weighed amount, determined by the highest rate to be tested, of
each test compound was placed in a 25 mL glass vial and was
dissolved in 4 mL of a 97:3 v/v (volume/volume) mixture of acetone
and dimethyl sulfoxide (DMSO) to obtain concentrated stock
solutions. If the test compound did not dissolve readily, the
mixture was warmed and/or sonicated. The concentrated stock
solutions obtained were diluted with 20 mL of an aqueous mixture
containing acetone, water, isopropyl alcohol, DMSO, Atplus 411F
crop oil concentrate, and Triton X-155 surfactant in a
48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain spray solutions
containing the highest application rates. Additional application
rates were obtained by serial dilution of 12 mL of the high rate
solution into a solution containing 2 mL of 97:3 v/v
(volume/volume) mixture of acetone and dimethyl sulfoxide (DMSO)
and 10 mL of an aqueous mixture containing acetone, water,
isopropyl alcohol, DMSO, Atplus 411F crop oil concentrate, and
Triton X-155 surfactant in a 48.5:39:10:1.5:1.0:0.02 v/v ratio to
obtain 1/2.times., 1/4.times., 1/8.times. and 1/16.times. rates of
the high rate. Compound requirements are based upon a 12 mL
application volume at a rate of 187 L/ha. Formulated compounds were
applied to the plant material with an overhead Mandel track sprayer
equipped with a 8002E nozzles calibrated to deliver 187 L/ha over
an application area of 0.503 square meters at a spray height of 18
inches (43 cm) above the average plant canopy height. Control
plants were sprayed in the same manner with the solvent blank.
The treated plants and control plants were placed in a greenhouse
as described above and watered by sub-irrigation to prevent
wash-off of the test compounds. After 14 days, the condition of the
test plants as compared with that of the untreated plants was
determined visually and scored on a scale of 0 to 100 percent where
0 corresponds to no injury and 100 corresponds to complete
kill.
By applying the well-accepted probit analysis as described by J.
Berkson in Journal of the American Statistical Society, 48, 565
(1953) and by D. Finney in "Probit Analysis" Cambridge University
Press (1952), the above data can be used to calculate GR.sub.50 and
GR.sub.80 values, which are defined as growth reduction factors
that correspond to the effective dose of herbicide required to kill
or control 50 percent or 80 percent, respectively, of a target
plant.
Some of the compounds tested, application rates employed, plant
species tested, and results are given in Table 1 and Table 2.
TABLE-US-00013 TABLE 1 Post-emergent Weed Control ##STR00015## Rate
% Control Compound # M Q W X Y Z (g ai/ha) CHEAL ABUTH HELAN 1
OCH.sub.3 Cl F OCH.sub.2CH.sub.3 Cl H 140 100 100 100 3 OCH.sub.3
Cl F OCH.sub.3 Cl H 140 100 100 100 4 OCH.sub.3 Cl F SCH.sub.3 Cl H
140 65 100 100 5 OCH.sub.3 Cl F H Cl OCH.sub.3 140 100 95 95 6
OCH.sub.3 Cl Cl OCH.sub.3 Cl H 140 100 95 100 7 OCH.sub.3 Cl F
CF.sub.2H Cl H 140 100 80 100 8 OCH.sub.3 Cl F N(CH.sub.3).sub.2 Cl
H 140 100 100 100 9 OCH.sub.3 Cl F OCH.sub.2O H 140 90 95 100 10
OCH.sub.3 Cl F OCH.sub.2CF.sub.2H Cl H 140 85 75 80 11 OCH.sub.3 Cl
F CH.sub.3 Cl H 140 95 95 100 12 OCH.sub.3 F F OCH.sub.3 Cl H 140
95 85 100 13 OCH.sub.3 Br F OCH.sub.3 Cl H 140 100 100 100 14
OCH.sub.3 Cl F SCF.sub.3 Cl H 140 50 80 90 15 OH Cl F OCH.sub.3 Cl
H 140 100 100 100 16 OH Cl F SCH.sub.3 Cl H 140 15 85 100 17 OH Cl
F H Cl OCH.sub.3 140 100 50 80 18 OH Cl Cl OCH.sub.3 Cl H 140 100
75 95 19 OH Cl F OCH.sub.2CH.sub.3 Cl H 140 90 95 95 20 OH Cl F
CH.sub.3 Cl H 140 100 90 100 21 OH Cl F OCH.sub.2CF.sub.2H Cl H 140
90 0 80 22 OH Cl F OCH.sub.2O H 140 95 80 90 23 OH Cl F
N(CH.sub.3).sub.2 Cl H 140 100 95 95 24 OH Cl F CF.sub.2H Cl H 140
95 80 90 25 OH Br F OCH.sub.3 Cl H 140 100 95 100 CHEAL =
lambsquarter (Chenopodium album) ABUTH = velvetleaf (Abutilon
theophrasti) HELAN = sunflower (Helainthus annuus)
TABLE-US-00014 TABLE 2 Post-emergent Weed Control ##STR00016## Com-
Rate pound (g ai/ % Control # M Q W X Y ha) CHEAL ABUTH HELAN 2
OCH.sub.3 Cl F OCH.sub.3 Cl 140 100 90 100 CHEAL = lambsquarter
(Chenopodium album) ABUTH = velvetleaf (Abutilon theophrasti) HELAN
= sunflower (Helainthus annuus)
40. Evaluation of General Preemergence Herbicidal Activity
Seeds of the desired test plant species were planted in a soil
matrix prepared by mixing a loam soil (43 percent silt, 19 percent
clay, and 38 percent sand, with a pH of about 8.1 and an organic
matter content of about 1.5 percent) and sand in a 70 to 30 ratio.
The soil matrix was contained in plastic pots with a surface area
of 113 square centimeters. When required to ensure good germination
and healthy plants, a fungicide treatment and/or other chemical or
physical treatment was applied.
A weighed amount, determined by the highest rate to be tested, of
each test compound was placed in a 25 mL glass vial and was
dissolved in 6 mL of a 97:3 v/v (volume/volume) mixture of acetone
and DMSO to obtain concentrated stock solutions. If the test
compound did not dissolve readily, the mixture was warmed and/or
sonicated. The stock solutions obtained were diluted with 18 mL of
a 0.1% v/v aqueous solution of Tween.RTM. 20 surfactant to obtain
spray solutions containing the highest application rate. Additional
application rates were obtained by serial dilution of 12 mL of the
high rate solution into a solution containing 3 mL of 97:3 v/v
mixture of acetone and DMSO and 9 mL of the 0.1% v/v aqueous
solution of Tween.RTM. 20 surfactant to obtain 1/2.times.,
1/4.times., 1/8.times. and 1/16.times. rates of the high rate.
Compound requirements are based upon a 12 mL application volume at
a rate of 187 L/ha. Formulated compounds were applied to the plant
material with an overhead Mandel track sprayer equipped with a
8002E nozzles calibrated to deliver 187 L/ha over an application
area of 0.503 square meters at a spray height of 18 inches (43 cm)
above the soil surface. Control plants were sprayed in the same
manner with the solvent blank.
The treated pots and control pots were placed in a greenhouse
maintained with an approximate 15 hour photoperiod and temperatures
of about 23-29.degree. C. during the day and 22-28.degree. C.
during the night. Nutrients and water were added on a regular basis
and supplemental lighting was provided with overhead metal halide
1000-Watt lamps as necessary. The water was added by
top-irrigation. After 20-22 days, the condition of the test plants
that germinated and grew as compared with that of the untreated
plants that emerged and grew was determined visually and scored on
a scale of 0 to 100 percent where 0 corresponds to no injury and
100 corresponds to complete kill or no emergence.
Some of the compounds tested, application rates employed, plant
species tested, and results are given in Table 3.
TABLE-US-00015 TABLE 3 Pre-emergent Weed Control Rate % Control
Compound # (g ai/ha) CHEAL ABUTH HELAN 2 140 90 100 20 6 140 100 60
90 7 140 70 75 90 10 280 60 80 0 11 140 60 100 100 15 140 100 100
100 16 140 50 80 80 17 140 95 100 0 18 140 100 100 100 19 280 75 80
90 CHEAL = lambsquarter (Chenopodium album) ABUTH = velvetleaf
(Abutilon theophrasti) HELAN = sunflower (Helianthus annuus)
41. Evaluation of Postemergence Herbicidal Activity in Cereal
Crops
Seeds of the desired test plant species were planted in Sun Gro
MetroMix.RTM. 306 planting mixture, which typically has a pH of 6.0
to 6.8 and an organic matter content of about 30 percent, in
plastic pots with a surface area of 103.2 square centimeters. When
required to ensure good germination and healthy plants, a fungicide
treatment and/or other chemical or physical treatment was applied.
The plants were grown for 7-36 days in a greenhouse with an
approximate 14 hour photoperiod which was maintained at about
18.degree. C. during the day and 17.degree. C. during the night.
Nutrients and water were added on a regular basis and supplemental
lighting was provided with overhead metal halide 1000-Watt lamps as
necessary. The plants were employed for testing when they reached
the second or third true leaf stage.
A weighed amount, determined by the highest rate to be tested, of
each test compound was placed in a 25 mL glass vial and was
dissolved in 8 mL of a 97:3 v/v mixture of acetone and DMSO to
obtain concentrated stock solutions. If the test compound did not
dissolve readily, the mixture was warmed and/or sonicated. The
concentrated stock solutions obtained were diluted with 16 mL of an
aqueous mixture containing acetone, water, isopropyl alcohol, DMSO,
Agri-dex crop oil concentrate, and Triton X-77 surfactant in a
64.7:26.0:6.7:2.0:0.7:0.01 v/v ratio to obtain spray solutions
containing the highest application rates. Additional application
rates were obtained by serial dilution of 12 mL of the high rate
solution into a solution containing 4 mL of 97:3 v/v mixture of
acetone and DMSO and 8 mL of an aqueous mixture containing acetone,
water, isopropyl alcohol, DMSO, Agri-dex crop oil concentrate, and
Triton X-77 surfactant in a 48.5:39.0:10.0:1.5:1.0:0.02 v/v ratio
to obtain 1/2.times., 1/4.times., 1/8.times. and 1/16.times. rates
of the high rate. Compound requirements are based upon a 12 mL
application volume at a rate of 187 L/ha. Formulated compounds were
applied to the plant material with an overhead Mandel track sprayer
equipped with a 8002E nozzles calibrated to deliver 187 L/ha over
an application area of 0.503 square meters at a spray height of 18
inches (43 cm) above average plant canopy height. Control plants
were sprayed in the same manner with the blank.
The treated plants and control plants were placed in a greenhouse
as described above and watered by sub-irrigation to prevent
wash-off of the test compounds. After 20-22 days, the condition of
the test plants as compared with that of the untreated plants was
determined visually and scored on a scale of 0 to 100 percent where
0 corresponds to no injury and 100 corresponds to complete
kill.
Some of the compounds tested, application rates employed, plant
species tested, and results are given in Table 4.
TABLE-US-00016 TABLE 4 Post-emergent Control of Several Key Weeds
in Wheat and Barley Rate % Control Compound # (g ai/ha) TRZAS HORVS
GALAP LAMPU PAPRH VERPE 1 35 0 0 99 85 100 20 2 35 0 0 95 95 100 50
3 17.5 0 0 95 99 100 99 6 70 10 0 85 99 99 99 7 17.5 15 0 60 90 95
95 8 35 15 0 70 85 100 95 9 70 15 0 90 100 40 30 10 70 5 0 65 85 95
20 13 17.5 0 0 90 95 100 95 TRZAS = wheat (Triticum aestivum) HORVS
= barley (Hordeum vulare) GALAP = Galium aparine LAMPU = Lamium
purpureum PAPRH = Papaver rhoeas VERPE = Veronica persica
42. Evaluation of Herbicidal Activity in Transplanted Paddy
Rice
Weed seeds or nutlets of the desired test plant species were
planted in puddled soil (mud) prepared by mixing a non-sterilized
mineral soil (28 percent silt, 18 percent clay, and 54 percent
sand, with a pH of about 7.3 to 7.8 and an organic matter content
of about 1.0 percent) and water at a ratio of 100 kg of soil to 19
L of water. The prepared mud was dispensed in 250 mL aliquots into
480 mL non-perforated plastic pots with a surface area of 91.6
square centimeters leaving a headspace of 3 centimeters in each
pot. Rice seeds were planted in Sun Gro MetroMix.RTM. 306 planting
mixture, which typically has a pH of 6.0 to 6.8 and an organic
matter content of about 30 percent, in plastic plug trays.
Seedlings at the second or third leaf stage of growth were
transplanted into 650 mL of mud contained in 960 mL non-perforated
plastic pots with a surface area of 91.6 square centimeters 4 days
prior to herbicide application. The paddy was created by filling
the 3 centimeter headspace of the pots with water. When required to
ensure good germination and healthy plants, a fungicide treatment
and/or other chemical or physical treatment was applied. The plants
were grown for 4-14 days in a greenhouse with an approximate 14
hour photoperiod which was maintained at about 29.degree. C. during
the day and 26.degree. C. during the night. Nutrients were added as
Osmocote (17:6:10, N:P:K+minor nutrients) at 2 g (grams) per cup.
Water was added on a regular basis to maintain the paddy flood, and
supplemental lighting was provided with overhead metal halide
1000-Watt lamps as necessary. The plants were employed for testing
when they reached the second or third true leaf stage.
A weighed amount, determined by the highest rate to be tested, of
each test compound was placed in a 120 mL glass vial and was
dissolved in 20 mL of acetone to obtain concentrated stock
solutions. If the test compound did not dissolve readily, the
mixture was warmed and/or sonicated. The concentrated stock
solutions obtained were diluted with 20 mL of an aqueous mixture
containing 0.01% Tween 20 (v/v). Application rates of 1/2.times.,
1/4.times., 1/8.times. and 1/16.times. of the high rate were
obtained by injecting an appropriate amount of the stock solution
into the aqueous layer of the paddy. Control plants were treated in
the same manner with the solvent blank.
The treated plants and control plants were placed in a greenhouse
as described above and water was added as needed to maintain a
paddy flood. After 20-22 days, the condition of the test plants as
compared with that of the untreated plants was determined visually
and scored on a scale of 0 to 100 percent where 0 corresponds to no
injury and 100 corresponds to complete kill.
Some of the compounds tested, application rates employed, plant
species tested, and results are given in Table 5.
TABLE-US-00017 TABLE 5 Water-injected Control of Several Key Weeds
in Rice Rate % Control Compound # (g ai/ha) ORYSA SCPJU CYPDI MOOVA
1 17.5 5 50 95 100 2 70 0 20 75 100 3 17.5 0 80 99 100 6 17.5 0 --
90 100 7 140 0 90 100 100 8 35 0 10 95 100 9 35 0 70 100 99 10 140
0 40 95 100 13 70 0 60 85 100 ORYSA = rice (Orysa sativa var.
Japonica) SCPJU = Scirpus juncoides CYPDI = Cyperus difformis MOOVA
= Monochoria vaginalis
* * * * *